Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][C:16]([C:20]([O-:22])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[CH3:23]CO>[Pd]>[NH2:11][C:12]12[CH2:19][C:16]([C:20]([O:22][CH3:23])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2
Reactant: O=C(NC12CCCC(C(=O)[O-])(CC1)C2)OCc1ccccc1
Reactant: CCO
Agent: [Pd]
Product: COC(=O)C12CCCC(N)(CC1)C2
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate (10 g, 31.5 mmol) in EtOH (50 mL) was added Pd/C (900 mg) under H2 atmosphere at room temperature and stirred overnight. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to afford 5.5 g (96%) of the crude title compound, methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate, as a colorless oil. ESI-MS m/z: 184 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25])=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=4[C:24]#[N:25])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: N#Cc1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: N#Cc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-formylbenzonitrile was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 2-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:20]1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][CH:20]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3c[nH]c4ccccc34)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(1H-indol-3-yl)-acrylic acid. LC-MS-conditions 05b: tR=0.84 min; [M+H]+=375.31.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[N:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:15]([CH3:25])[N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:25][C:15]1[N:14]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH:18]=[N:17][C:16]=1[O:19][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: Cc1nc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1nc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (250 mg, brown solid) from 4-chloro-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (270 mg, 0.72 mmol, Intermediate-84) and phenyl formate (180 mg, 1.4 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:23]=[CH:22][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:24][S:25]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].[CH2:34]=O>C(O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:12])=[CH:22][CH:23]=2)=[N:4][C:3]=1[CH2:24][S:25]([CH:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: C=O
Reactant: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Solvent: O=CO
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C)CC1
Reaction time: 0.2 h
Yield: 11 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide (322 mg, 0.69 mmol, 1.00 equiv) and paraformaldehyde (0.21 g, 10.00 equiv) in formic acid (15 mL) was stirred overnight at 110° C. The resulting mixture was concentrated under vacuum and the crude product (320 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, CH3CN/H2O (5% up to 60% in 12 min, up to 100% in 1 min, down to 5% in 1 min); Detector, UV 254 nm, to give 36.5 mg (11%) of 4-[5-methyl-4-[(1-methylpiperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide as a white solid. LC-MS: (ES, m/z): 483 [M-PH]+, 242. 1HNMR (400 MHz, CD3OD, ppm): δ 8.47 (s, 1H), 8.42-8.40 (s, 1H), 8.08-8.06 (d, 2H), 7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (m, 1H), 4.41 (s, 2H), 3.69-3.66 (t, 2H), 3.21-3.06 (m, 1H), 3.06-2.99 (m, 4H), 2.50 (s, 3H), 2.30 (s, 3H), 2.26-2.23 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(Nc2c(Cl)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Product: Cc1ccc(N(C(=O)CCl)c2c(Cl)cccc2Cl)cc1

Procedure:
N-(2′,6′-Dichlorophenyl)-4-methylaniline (4.86 g) is reacted with chloroacetylchloride (3.92 g) at 90° C. for 2 h. After dilution with toluene, the mixture is washed with aqueous sodiumcarbonate twice, 40% aqu. sodium bisulfite and water. The organic phase is dried (MgSO4) and evaporated. The residue is recrystallised from ethanol (12 g) to obtain N-(2′,6′-Dichlorophenyl)-N-chloroacetyl (2.83 g), mp: 129.5-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
A 100 mL round-bottom flask was charged with 4-bromopyridine-2-carbaldehyde (1.60 g, 8.60 mmol, 1.07 equiv), tert-butyl piperazine-1-carboxylate (1.50 g, 8.05 mmol, 1.00 equiv), and dichloromethane (30 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (5.10 g, 24.1 mmol, 3.00 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (2×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (45/55) to provide 2.70 g (94% yield) of tert-butyl 4-[(4-bromopyridin-2-yl)methyl]piperazine-1-carboxylate as a yellow solid. LCMS (ESI, m/z): 356 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][C:22]([CH3:25])([CH3:26])[CH2:21][CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 0.1 %

Procedure:
To a solution of N-isopropyl-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 227 mmol) in dichloromethane (3 mL) was added TFA (1.48 g, 1 mL, 13.0 mmol). The reaction mixture was stirred at 25° C. for 15 h then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide; 60:10:1 and stirred at 25° C. for 3 h, then evaporated to a yellow solid. The solid was dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (40 g, 50 μm particle size, Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane, 15 min). The pure product was re-dissolved in MeOH and allowed to stand for solid formation. The solid was separated by decanting the mother liquors and then dried to give N-isopropyl-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 164 μmol, 72%) as a white needles. MS (M+H)+=367; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.47-12.74 (m, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 7.92 (d, J=8.31 Hz, 1H), 4.07-4.48 (m, 1H), 3.78 (s, 3H), 2.72 (s, 2H), 2.64 (t, J=6.42 Hz, 2H), 1.60 (t, J=6.42 Hz, 2H), 1.26 (d, J=6.42 Hz, 6H), 1.01 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(=Cc2ccccc2)CC1

Procedure:
In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfuric acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19](O)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH2:8][CH3:9])=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CCN1CCCC1CN
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)Cc1ccc(Cl)c(Cl)c1
Yield: 96.4 %

Procedure:
2-Aminomethyl-1-(ethyl)pyrrolidine (Aldrich) (3.2 g, 25 mmol) and 3,4-dichlorophenylacetic acid (7.7 g, 37.6 mmol, 1.5 eq) were coupled in CH2Cl2 in the presence of DCC (10.6 g, 51 mmol, 2 eq) as described in Example 7 to give the desired product (7.6 g, 97%) as a colorless oil: 1H-NMR (CDCl3) ∂7.41 (d, J=8.2 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.13 (dd, J=2.0, 8.2 Hz, 1H), 6.13 (br s, 1H), 3.51 (s, 2H), 3.37 (m, 1H), 3.07 (m, 2H), 2.65 (m, 1H), 2.53 (m, 1H), 2.04-2.21 (m, 2H, CH2CH3 ), 1.81 (m, 1H), 1.67 (m, 1H), 1.35-1.60 (complex m, 2H), 0.99 (t, J=7.2 Hz, 3H); CIMS (MH+ calcd for C15H20Cl2N2O): 315. Found (MH+): 315; Anal. (calcd for C15H20Cl2N2O): C,H,N.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(NC(C)=O)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (from Combi-Blocks). LCMS calculated for C23H24N5O3(M+H)+: m/z=418.2. Found 418.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:53](Cl)(=[O:55])[CH3:54].O>ClCCl>[C:53]([O:38][C@@H:36]1[C@H:35]([OH:39])[C:34]([CH3:41])([CH3:40])[C@H:33]2[C@@:27]3([O:26][C:11]4[C:12]5[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=5[CH:17]=[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:10]=4[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32]2)[CH2:37]1)(=[O:55])[CH3:54]
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@H]1C[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CN(C(=O)OC(C)(C)C)C5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C(C)(C)[C@H]1O
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of Compound (48a) (51 mg, 0.086 mmol) in 5.0 ml of dichloromethane were added 32 mg (0.26 mmol) of dimethylaminopyridine and 9.2 μl (0.13 mmol) of acetyl chloride under ice-cooling, and the mixture stirred for 30 min at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated hydrogen carbonate solution, and water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; toluene:ethyl acetate=2:1) to give 49 mg (90%) of Compound (48b).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[I-].[CH3:32][S+](C)C.CC(C)([O-])C.[K+]>O1CCCC1.CS(C)=O>[O:30]1[C:27]2([CH2:26][CH2:25][CH:24]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[CH:9]3)[CH2:29][CH2:28]2)[CH2:32]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC2(CC1)CO2
Temperature: -5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (2 g, 5 mmol) in tetrahydrofuran (17.5 mL) were added trimethyl-sulfonium iodide (1.53 g, 7.5 mmol) in dimethyl sulfoxide (25 mL) and potassium-t-butoxide (7.5 mL, 7.5 mmol, 1 M in tetrahydrofuran) under an atmosphere of nitrogen at −5° C. The mixture was stirred at −5° C. for 1 hour. The mixture was poured into ice water (50 mL). The water phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated ammonium chloride solution (2×30 mL), water (1×30 mL), and brine (2×30 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 7-(1-oxaspiro[2.5]oct-6-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.9 g, 4.6 mmol, 2:1-mixture of trans and cis). The mixture was suspended in dichloromethane (3 mL). The solid was filtered and was washed with dichloromethane (1 mL) to yield 7-(1-oxaspiro[2.5]oct-6-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.994 g, 2.4 mmol, 4:1-mixture of trans and cis).
Reaction SMILES: [OH-].[Na+].C(O)(=O)C.[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]([CH3:20])[C:15]([O:17]CC)=[O:16]>C(O)C>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)[C@H](C)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](OC1CCCCO1)C(=O)O

Procedure:
In ethanol (450 ml) was dissolved ethyl(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate, to which was added, under ice-cooling, 2N sodium hydroxide solution (150 ml), and the mixture was stirred for one hour at room temperature. The reaction mixture was cooled with ice, to which was added a 27° C. aqueous solution of acetic acid (100 ml), followed by extraction with dichloromethane (200 ml) three times. Dichloromethane layers were combined and washed with a saturated aqueous saline solution (100 ml) twice, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave (2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (29.5 g) as a colorless waxy product.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13](OC)=[O:14])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Yield: 108 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydoxy-2-methoxycarbonylpyrrolidine (10 g) in tetrahydrofuran (20 ml) and ethanol (30 ml) was added by portions sodium borohydride (3.30 g) with stirring at 25°-30° C., and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture was added dropwise conc. hydrochloric acid (7.27 ml) with stirring at 0°-2° C. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of tetrahydrofuran (20 ml), ethanol (20 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-hydroxymethylpyrrolidine (9.48 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][N:23]=2)=[O:18])=[C:10]([CH3:31])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:31])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][N:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-{[(5-Benzyl-oxazole-2-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (170 mg, 0.34 mmol), 2 mL TFA and 5 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the crude product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 8.80 (t, 1H), 7.27-7.37 (m, 5H), 7.10 (s, 1H), 6.11 (s, 1H), 5.72 (s, 2H), 4.31 (d, 2H), 4.12 (s, 2H), 2.30 (s, 3H), 2.17 (s, 3H); LCMS (method A) RtA=1.001 min; [M+H]+=337.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH:34]C(OCC1C=CC=CC=1)=O)[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH2:34])[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H](N)Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21
Reaction time: 5 h

Procedure:
878 mg of the compound of example 1, step d) were dissolved in 50 ml of methanol and 0.4 ml of acetic acid. Under a nitrogen atmosphere 350 mg of 10% palladium on charcoal were carefully added, and hydrogenation was performed under shaking of the reaction vessel. After 5 hours the reaction was complete. The solvents were removed after filtration of the catalyst Yield: 680 mg of a resinous product. MS (ES+): m/e=479.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Cl[C:14]1[N:15]([CH3:27])[C:16](=[O:26])[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[N:19]=1>O1CCCC1>[CH3:27][N:15]1[C:16](=[O:26])[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[N:19]=[C:14]1[O:3][CH2:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: O=C(CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(OCC(=O)c2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a suspension of sodium hydride (60 wt % in oil, 0.23 g, 6.3 mmol) in tetrahydrofuran (5 ml) was added 2-hydroxyacetophenone (0.92 g, 6.75 mmol) in tetrahydrofuran (5 ml) and the mixture was stirred at room temperature. After 30 minutes, 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (1.0 g, 4.5 mmol) was added. The mixture was stirred under reflux for 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-(2-oxo-2-phenyl-ethoxy)-1H-[4,4′]bipyrimidinyl-6-one (75 mg, 0.23 mmol, 5%) as a colorless solid.