Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:23]([CH:31]1[O:35][C:34]2[CH:36]=[CH:37][C:38]([CH2:40]O)=[CH:39][C:33]=2[O:32]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:40][C:38]3[CH:37]=[CH:36][C:34]4[O:35][CH:31]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:32][C:33]=4[CH:39]=3)=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Oc2ccc(CO)cc2O1
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCc3ccc4c(c3)OC(CCCCCCCC)O4)cc2)nc1

Procedure:
By Mitsunobu etherification of 4-(5-octyloxypyrimidin-2-yl)phenol using (2-octylbenzo[1,3]dioxol-5-yl)methanol.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12](=[O:30])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH:31]([Sn](CCCC)(CCCC)CCCC)=[CH2:32].[Cl-].[Li+]>O1CCOCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([S:7]([C:5]3[S:6][C:2]([CH:31]=[CH2:32])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH2:11][C:12]2=[O:30])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Br)s3)CC2=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C2)s1
Yield: 116.3 %

Procedure:
A mixture of 4-(5-bromo-2-thiophenesulfonyl)-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (200 mg), vinyltributyltin (365 mg), lithium chloride (50 mg), tetrakistriphenylphosphine palladium (50 mg) and dioxane (15 ml) was refluxed for 2 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane: ethyl acetate=1:2) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(5-vinyl-2-thiophenesulfonyl)-2-piperazinone (209 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1([CH2:33][O:34][CH3:35])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2([CH2:33][O:34][CH3:35])[CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: COCC1(CBr)CC1
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with 1-bromomethyl-1-methoxymethyl-cyclopropane (prepared as described in WO 2001032633) gave the title compound.
Reaction SMILES: [C:1]1([C@@H:7](NC[C@@H](CCC)CC(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][CH2:23][CH3:24])(=O)C.Cl>CO>[CH:1]1[CH:6]=[C:5]2[CH:4]=[CH:24][C:23]([OH:22])=[C:7]([C:1]3[C:2]4[C:3](=[CH:8][CH:7]=[CH:23][CH:24]=4)[CH:4]=[CH:5][C:6]=3[OH:22])[C:8]2=[CH:3][CH:2]=1
Reactant: CCC[C@H](CN[C@@H](C)c1ccccc1)CC(=O)O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in methanol (20 mL) and (RS)-1,1′-bi-2-naphthol (5.75 g) is added to it at room temperature. The mixture is stirred at 50° C. for 1 hour, during which time solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under reduced pressure to obtain 3.5 g of solid complex. Complex is suspended in the biphasic mixture of ethyl acetate (20 ml) and 1N hydrochloric acid (20 ml) and stirred for 30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to obtain optically pure (5)-1,1′-bi-2-naphthol (1.5 g) having 99% ee.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[N:1]1([C:11]([C@@H:7]2[CH2:8][CH2:9][CH2:10][O:6]2)=[O:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(Cl)[C@@H]1CCCO1
Solvent: ClC(Cl)Cl
Product: O=C([C@@H]1CCCO1)n1ccnc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
21.8 g (32.0 mmol) imidazole are placed in 400 ml chloroform and cooled to 0° C. 21.5 g (15.0 mmol) (S)-tetrahydrofuran-2-carbonyl chloride are added dropwise, then stirred for 1.5 hours at ambient temperature. After cooling again to 0° C. the reaction mixture is extracted with semisaturated sodium chloride solution. The organic phase is dried and evaporated to dryness. Yield: 23.5 g
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].BrC[CH2:16][CH:17]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[CH2:19][O:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][NH:8][CH2:16][CH:17]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[CH2:19][O:18]1)[CH2:11][CH2:12][CH3:13]
Reactant: CC1COC(CCBr)OC1C
Reactant: CCCCOC(CN)OCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOC(CNCC1OCC(C)C(C)O1)OCCCC
Temperature: 25 °C

Procedure:
2,2-Dibutoxyethylamine (0.11 mole), 2-bromoethyl-4,5-dimethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-amine.
Reaction SMILES: C[C@H]([NH:36][C:37]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=O)C(N[C@H](C(N1[C@H](C(N[C@H](C(SCC2C=CC=CC=2)=O)CC2C=CC=CC=2)=O)CCC1)=O)C)=O.FC(F)(F)[C:46]([O-:48])=[O:47]>>[NH2:36][C@H:37]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][C:41](=[O:42])[OH:43]
Reactant: C[C@H](NC(=O)CCC(=O)O)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)SCc1ccccc1
Reactant: O=C([O-])C(F)(F)F
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
First, 10 g of carboxypeptidase B (Sigma) was added to 100 pl of a solution of the (Glu-OC)-Lys monomers obtained in the above step (6), and the mixture was left for 2 hr at 37° C. Then the reaction was stopped by the addition of 50.1 of 0.1% trifluoroacetate solution. The mixture was separated by high-pressure liquid chromatography with use of a C18 reversed-phase column, and Glu-OC was obtained quantitatively.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C[O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1>C(OCC)C>[OH:14][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][C:8]([C:7]([OH:16])=[O:6])=[CH:9][C:10]=1[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)c(C)c1
Solvent: CCOCC
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.4 %

Procedure:
65% aq. nitric acid solution (2.7 mL, 60 mmol) and fuming nitric acid (2.5 mL, 60 mmol) were added at −10° C. to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester (4.97 g, 29.9 mmol) in diethyl ether (60 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to afford 4-hydroxy-3-methyl-5-nitro-benzoic acid (6.27 g, 99%). Yellow solid, MS (ISP)=210.1 (M−H)−.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](=[O:18])[NH:10][N:9]=1)=[O:6]>CO>[C:5]([CH2:7][C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](=[O:18])[NH:10][N:9]=1)([OH:6])=[O:4]
Reactant: COC(=O)Cc1n[nH]c(=O)c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1n[nH]c(=O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
5N sodium hydroxide solution (1.72 mL) was added dropwise to a suspension of the compound prepared in Example 15 (635 mg) in methanol (10.0 mL) in ice bath and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrate. 2N hydrochloric acid was added to the residue, which was adjusted to pH 2. The deposited crystal was collected by filtration. It was washed with hexane and dried under reduced pressure to give the title compound (478 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][O:17][CH3:18].O=P(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2c(=O)[nH]cnc2cc1OC
Solvent: Cc1ccccc1
Product: COCCOc1cc2c(Cl)ncnc2cc1OC
Temperature: 125 °C
Yield: 69 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one (0.6 g, 2.4 mmol) and POCl3 (1 mL) in toluene (10 mL) was heated at 125° C. for 2 hours, to afford 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline as solid (0.445 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 4.33 (t, 2H), 4.03 (s, 3H), 3.77 (t, 2H), 3.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:24][C:22]1[NH:21][N:20]=[C:19]([NH:18][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:25])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)[N:17]=2)[CH:23]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(N)cc3)c(=O)c3ccccc23)n[nH]1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-n2nc(Nc3cc(C)[nH]n3)c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Amino-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (C-2, 0.050 g, 0.15 mmol) was dissolved in pyridine (1 ml) at 0° C. Acetylchloride (0.024 ml, 0.33 mmol) was added and stirring was continued for 30 min at 0° C. before the mixture was allowed to warm to room temperature. The solvent was evaporated after 2 h stirring at room temperature. The residue was diluted in MeOH (1 ml) and treated with conc. NH3 (1 ml). The title compound was obtained after stirring at room temperature for 24 h and evaporation of the solvents in vacuum (0.016 g, 29%). 1H-NMR: (400 MHz, D6-DMSO) 11.93 (1H, s), 10.08 (1H, s), 9.26 (1H, s), 8.49 (1H, d), 8.36 (1H, d), 7.88–7.98 (2H, m), 7.61–7.69 (4H, m), 6.24 (1H, s), 2.19 (3H, s), 2.08 (3H, s); MS (API+)=375 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:25]=1[CH3:26]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:25]=2[CH3:26])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 147E]) to give the title compound as light brown oil.
Reaction SMILES: C1CO[CH:8]2[CH:3]([CH2:4][C:5](=[O:24])[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18]C(N=[N+]=[N-])=O)([CH3:11])[CH2:7]2)[O:2]1.C(O)(=O)C.C[N:30](C)C=O>>[O:24]=[C:5]1[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][C:6]1([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:30])[CH3:11]
Reactant: CC1(c2ccccc2CC(=O)N=[N+]=[N-])CC2OCCOC2CC1=O
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(c2ccccc2CN)CCC(=O)CC1=O
Temperature: 100 °C

Procedure:
The acyl azide 5 is dissolved in dimethylformamide and heated to 100° C. until nitrogen evolution ceases. The solution is cooled and treated with aqueous acetic acid to form 2-(2', 4'-dioxo-1'-methyl-cyclohexyl)-benzyl amine 6. Diethyl ether is added and the solution is washed successively with saturated sodium bicarbonate solution, water, and saturated salt solution and dried over anhydrous sodium sulfate. The solvent is removed by rotoevaporation to yield 1,2,3,4,4a,5,6,10b-octahydro- 10b-methyl-3-phenanthridinone 7.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
Under argon stream, 3.53 ml (25 mmol) of trimethylsilylacetylene was dissolved in 25 ml of tetrahydrofuran and cooled to -78° C. Into the solution was added dropwise 145.9 ml (24 mmol) of butyllithium-hexane solution, and the reaction was carried out with stirring for 30 minutes. Then, 6.5 ml (24 mmol) of tributyltin chloride was added dropwise, and the reaction was carried out with stirring for 22 hours, while elevating gradually the temperature of the reaction mixture to room temperature. After the reaction, the solvent was evaporated and the residue was distilled under reduced pressure (0.6 mm Hg, 100°-102° C.) to obtain 4.84 g of a transparent liquid (yield: 52.2%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[CH:35][N:34]=[CH:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(Cn2ccnc2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3ccnc3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-imidazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](O)(=O)[CH3:36]>>[CH3:35][C:36]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1
Reactant: CC(=O)O
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 120 °C
Yield: 43 %

Procedure:
A mixture of N-[4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (100 mg, 0.21 mmol) and glacial acetic acid (0.5 mL) was heated at 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5) followed by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 172 as a white solid (45 mg, 43%). LCMS (method A): RT=5.65 min, M+H−=506.1. 1H NMR (CDCl3, 400 MHz) δ 8.08-8.03 (m, 1 H), 7.73-7.68 (m, 1 H), 7.30-7.26 (m, 3 H), 4.05 (t, J=4.8 Hz, 4 H), 3.99 (s, 2 H), 3.88 (t, J=4.8 Hz, 4 H), 3.73 (m, 4 H), 3.65 (s, 2 H), 3.18-2.99 (m, 3 H), 2.93 (s, 3 H), 2.34 (m, 4 H)
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>ClCCCl>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Clc1ncnc2sccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
Thieno[2,3-d]pyrimidin-4(3H)-one (1.2 g, 7.9 mmol) was diluted in 1,2-dichloroethane (10 mL). Phosphorous oxychloride (1.4 mL, 15.7 mmol) was added. The reaction was stirred at 90° C. for 16 hours. An additional equivalent of phosphorous oxychloride (0.7 mL, 7.9 mmol) was added and the solution continued stirring for 4 hours. The solution was cooled, concentrated, and neutralized with saturated NaHCO3 solution. The material was extracted with a chloroform:isopropyl alcohol mixture and the organic layer was separated and concentrated. Flash chromatography gave the title compound (0.39 g, 29%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=1)[C:20](=[O:30])[CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=1)[C:20](=[O:30])[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CCC(=O)OC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CCC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from example 18 (140 mg) was dissolved in DCM (1 ml) and TFA (0.2 ml) added. The mixture was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 solution and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 80 mg.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O>[CH:3]1([N:7]2[CH2:8][CH2:9][CH:10]([O:13][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC2CCN(C3CCC3)CC2)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of sodium hydride (24.76 g, 60% in mineral oil, 0.619 moles) in dimethylformamide (100 mL) was added 1-cyclobutyl-4-piperidinol (80 g, 0.516 moles, obtained in the above step) in dimethylformamide (300 mL) at 10° C. under a nitrogen atmosphere. The mass was stirred for 1 hour. A solution of 4-fluoronitrobenzene (87.3 g, 0.619 moles) in dimethylformamide (300 mL) was added drop wise to the above reaction mass at room temperature. After completion of reaction, the mass was quenched on to chilled water (2 L) and stirred for 1 hour. The obtained solids were separated and dissolved in ethyl acetate (1 L). The resulting ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The residue, thus obtained, was purified by flash chromatography (methanol:chloroform, 2:8) to afford the title compound 99.7 g (Yield: 70%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C1COCC1.CN(C=O)C>[CH:22]([NH:25][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.8 %

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Isopropylamine (511 μL, 6 mmol) was then added into the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography: SiO2, CH2Cl2/AcOEt 95:5 to give a white solid (167 mg, 58%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=7.68 Hz, 2H), 7.59 (d, J3=7.14 Hz, 2H), 7.50-7.33 (m, 4H), 5.93 (br. s., 1H), 4.14 (oct., J3=6.66 Hz, 1H), 1.27 (d, J=6.43 Hz, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([F:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][C:28]([CH3:33])([CH3:32])[O:29][C:30](=[O:31])[C:25]=2[CH:24]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:22][C:23]3[CH:35]=[CH:34][C:26]4[O:27][C:28]([CH3:32])([CH3:33])[O:29][C:30](=[O:31])[C:25]=4[CH:24]=3)=[C:15]([F:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)c(F)c2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)c(F)c2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]-2-fluorobenzaldehyde and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a yellow powder (66%). 1H NMR (CDCl3, 300 MHz) δ 7.41 (d, J=7.9 Hz, 2H), 7.38-7.12 (m, 6H), 6.90-6.76 (m, 2H), 4.39 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.68 (s, 6H), 1.65-1.52 (m, 2H). 1.41-1.17 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). M− (ESI): 456.1 HPLC, Rt: 5.66 min (Purity: 97.9%).