Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][CH2:8][C:9]1[NH:10][C:11](=[O:19])[C:12]2[CH2:18][O:17][CH2:16][CH2:15][C:13]=2[N:14]=1.[F:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:7]([CH2:8][C:9]3[NH:10][C:11](=[O:19])[C:12]4[CH2:18][O:17][CH2:16][CH2:15][C:13]=4[N:14]=3)[CH2:6][C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:35])[CH2:31][CH2:32]2)=[O:26])=[CH:37][CH:38]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNC[C@H]2CCCO2)nc2c1COCC2
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)C[C@H]2CCCO2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (20.2 mg) from (R)-2-(((tetrahydrofuran-2-yl)methylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H33FN4O4 512.6. found 513.7 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.89 (dd, J=8.84, 5.31 Hz, 2H) 7.11 (t, J=8.59 Hz, 2H) 4.52-4.69 (m, 1H) 4.28-4.52 (m, 4H) 4.09-4.28 (m, 3H) 3.77-3.95 (m, 5H) 3.62-3.74 (m, 2H) 3.28-3.45 (m, 4H) 2.54-2.62 (m, 1H) 2.19 (d, J=7.07 Hz, 1H) 2.12 (br. s., 3H) 1.84-2.02 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([O:22]CC)=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([OH:22])=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 60 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a solution of ethyl 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.41 g, 1.15 mmol) in MeOH (6 mL) was added a solution of sodium hydroxide (92 mg, 2.30 mmol) in 1 mL of water. The resulting mixture was stirred for 5 h at 60° C. The mixture was acidified to pH=6.5 by 1 N HCl and concentrated to afford the title product as brown solid (358 mg, 95% yield). LC-MS (APCl, M+H+): 329.1. HPLC: 96% purity.
Reaction SMILES: [Cl:1][C:2]1[C:17]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:5]2[O:6][CH:7]([CH2:9][N:10]=[N+]=[N-])[CH2:8][C:4]=2[CH:3]=1>[Pt]>[Cl:1][C:2]1[C:17]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(Cl)c3c(c2O1)CCC3
Agent: [Pt]
Product: NCC1Cc2cc(Cl)c3c(c2O1)CCC3
Yield: 77 %

Procedure:
Treatment of (±)-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (1.4 g, 3.70 mmol) with sodium azide (0.96 g, 14.78 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide as a crude oil. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.15 g) generally according to the procedure described for Example 2 provided 0.74 g (77%) of (±)-1-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 270° C. (dec); Anal. calcd. for C12H14ClNOHCl: C, 55.4; H, 5.81; N, 5.38. Found: C, 55.4; H, 5.8; N, 4.91.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][O:5][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
To a solution of 3,3,3-trifluoro-propan-1-ol (1.1 g, 10.0 mmol) in DCM (10 mL) are added p-toluenesulfonyl chloride (2.3 g, 12.0 mmol), N,N-dimethylaminopyridine (0.1 g, 1.0 mmol) and triethyl amine (2.8 mL, 20.0 mmol). The reaction is stirred at room temperature for 3 d, then poured into water and extracted with DCM. The combined organic extracts are washed with 1N aqueous HCl solution, saturated aqueous NaHCO3 solution, brine and dried over Na2SO4, filtered and concentrated to afford 2.34 g of title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.47 (3H, s), 2.47-2.6 (2H, m), 4.22 (2H, t, J=6.4 Hz), 7.36 (2H, d, J=8.08 Hz), 7.8 (2H, d, J=7.8 Hz)
Reaction SMILES: C(OC(C1CCCC1=O)=O)C.[H-].[Na+].C(Br)CCCCCCC.C([O:25][C:26]([C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:32][CH2:31][CH2:30][C:29]1=[O:33])=O)C.[BH4-].[Li+].OCC1(CCCCCCCC)CCCC1=O>CN(C)C=O.O1CCCC1.C(OC(=O)C)C.C(OCC)C.O>[OH:25][CH2:26][C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:32][CH2:31][CH2:30][CH:29]1[OH:33]
Reactant: CCCCCCCCC1(C(=O)OCC)CCCC1=O
Agent: CCCCCCCCC1(CO)CCCC1=O
Agent: CCOC(=O)C1CCCC1=O
Agent: [BH4-]
Solvent: CCCCCCCCBr
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC1(CO)CCCC1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
20 g of 2-ethoxycarbonyl-cyclopentanone was dissolved in 15 ml dimethylformamide and stirred. Then, a solution comprising 200 ml dimethylformamide with 6 g sodium hydride dispersed therein was gradually added dropwise to the above 2-ethoxycarbonyl-cyclopentanone solution. After the addition of the sodium hydride solution had been completed, the reaction solution was stirred for 2 hours at room temperature under a nitrogen gas stream. A solution comprising 15 ml dimethylformamide with 25 g octyl bromide dissolved therein was further added dropwise to the reaction solution. After the addition had been completed, the temperature was raised to 100° C. and agitation was conducted for 2 hours. The reaction solution was cooled down, then poured into iced water and extraction with 100 ml diethylether was conducted twice. The diethylether layer was dried with anhydrous sodium sulfate, and then the diethylether was removed to provide a crude reaction product of 2-ethoxycarbonyl-2-octyl-cyclopentanone. This crude reaction product was dissolved in 20 ml of tetrahydrofuran. A solution comprising 80 ml tetrahydrofuran with 2 g lithium borohydride dispersed therein was added dropwise to the above 2-ethoxycarbonyl-2-octyl-cyclopentanone solution under an iced condition while stirring and the stirring was further continued for 4 hours. After adding 50 ml ethylacetate and 100 ml distilled water, the solution was acidified by the addition of a 10% sulfuric acid aqueous solution to give a pH of 2. The reaction solution was extracted twice with 50 ml of diethylether. The diethylether layer was dried with anhydrous sodium sulfate, and then the diethylether was removed to provide a crude reaction product of 2-hydroxymethyl-2-octyl-cyclopentanone. This crude reaction product was purified by means of silica gel column chromatography (eluent: chloroform/methanol=97/3) and 18.9 g of 2-hydroxymethyl-2-octyl-cyclopentanol was obtained as a pale yellow, oily substance (yield: 64.7%). In the measurement of the infrared absorption spectrum, a strong absorption by a hydroxyl group at 3,370 cm−1 and, in the mass spectrometric measurement, a peak corresponding to the loss of water from the parent ion peak, were observed. Besides, in the elemental analysis, measured values of C=73.37% and H=12.45% were found (theoretical values of C and H: C=73.13% and H=12.35%). Thus, the production of 2-hydroxymethyl-2-octyl-cyclopentanol was ascertained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc(F)c1
Yield: 72.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-fluoro-phenylboronic acid (27 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (38 mg, 73%). LC-MS m/e 405.28 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH2:44])[CH2:39]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:38]2[CH2:39][C@H:40]([NH2:44])[CH2:41][CH2:42][CH2:43]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Reactant: N[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine dihydrochloride (11.5 gm) were added to the reaction mixture at 30° C. The reaction mixture was heated to 95° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30° C. and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution was added drop-wise at 30° C. The mixture was stirred for one hour at 30° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Isopropyl alcohol (100 mL) was added to the residue and stirred for 3 hours at room temperature. Filtered the compound and washed with isopropyl alcohol (20 mL) and dried the compound at below 60° C. under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: FIG. 2, Purity: 99.0%
Reaction SMILES: I[C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C[Si]([C:20]#[CH:21])(C)C.[OH-].[K+]>O1CCCC1.C(N(CC)CC)C.C(Cl)(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]([C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)#[CH:21]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cnc(NC(=O)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-iodo-4-methyl-2-trimethylacetylaminopyridine (176 mg, 0.55 mmol) in tetrahydrofuran (0.60 mL), triethyamine (3.32 mL), bis(triphenylphosphine)palladium(II) chloride (4 mg), copper(I) iodide (1.1 mg) and (trimethylsilyl)acetylene (117 uL, 0.83 mmol) were added. The mixture was stirred at room temperature for 3 h. The mixture was diluted with chloroform (50 mL), dried (Na2SO4), and evaporated to give a tan solid. The crude solid was dissolved in methanol (5 mL), treated with 1N potassium hydroxide (0.61 mL) and stirred at room temperature 18 h. The mixture was evaporated to dryness, dissolved in chloroform (50 mL), dried over Na2SO4, and evaporated to a solid. The product was purified by silica gel column chromatography using 10% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14](=[O:26])[C:13]([C:27](O)=[O:28])=[CH:12][C:11]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:1]1([CH2:7][NH:8][C:27]([C:13]2[C:14](=[O:26])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:10]([CH3:9])=[C:11]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:12]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccccc2)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NCC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2)cc(C(=O)NCC2CCCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
(Cyclohexylmethyl)amine in NMP (135 μl, 0.3M, 0.04 mmol) was added to a mixture of 6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydro-pyridine-3-carboxylic acid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), HOAT (7 mg, 0.04 mmol) and DIEA (13 mg, 0.1 mmol) in NMP (160 μl). The reaction mixture was stirred for 17 h at room temperature. The solvent was removed in vacuo, and the residue was dissolved in acetonitrile/water, 50/50, to a total volume of 1.6 ml, and purified using preparative HPLC to give the title compound (7 mg, 50%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]([O:23]C)=[O:22])=[CH:8][C:7]=1[C@H:27]1[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:31]([O:37][C:38](=[O:40])[CH3:39])[C@H:30]([O:41][C:42](=[O:44])[CH3:43])[C@@H:29]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:28]1)[CH3:4].Cl>CO>[CH2:3]([O:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]([OH:23])=[O:22])=[CH:8][C:7]=1[C@H:27]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:31]([O:37][C:38](=[O:40])[CH3:39])[C@@H:30]([O:41][C:42](=[O:44])[CH3:43])[C@@H:29]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:28]1)[CH3:4]
Reactant: CCOc1ccc(Cc2cc3cccccc-3c2C(=O)OC)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(Cc2cc3cccccc-3c2C(=O)O)cc1[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
10% aqueous solution of sodiumhydroxide (5.0 ml) was added dropwise to a solution of methyl 2-(4-ethoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy) methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.58 g) in methanol (5.0 ml) at room temperature. The mixture was stirred for 30 minutes and refluxed with heating for further six hours. After cooling with ice, the reaction mixture was neutralized by adding 10% aqueous solution of hydrochloric acid. The neutralized product was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 2-(4-ethoxy-3-[(2S,3R,4R,5S,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylic acid (0.4 g).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[C:9]1([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:19]1([CH:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]([NH:6][C:5]2[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=2)=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)C(c1ccccc1)c1ccccc1

Procedure:
To stirred suspension of (3 gr, 27 mmol) of cytosine (C) in 30 ml of dry pyridine at room temperature (6.85 g, 29.7 mmol) of diphenylacetyl chloride were added in portions. The reaction mixture was stirred at room temperature overnight. TLC indicated the end of the reaction. 2 ml of water was added and the solvent was evaporated under reduced pressure. 100 ml of water were added to the residue and the mixture was stirred vigorously for 30 minutes. The desired product (11) was precipitate and filtered. The white precipitate was washed with 100 ml of ether and dried.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH3:37])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH3:37])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 70 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(ethylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 5, preparation of starting materials) to give the title compound in 70% yield; NMR spectrum (DMSO-d6) 1.10 (t, 3H), 3.29-3.45 (m, 2H), 3.80-3.95 (m, 2H), 4.10 (s, 2H), 4.30-4.55 (m, 2H), 4.42 (t, 1H), 5.30 (s, 2H), 7.18 (d, 1H), 7.22 (d, 1H), 7.30-7.40 (m, 2H), 7.60 (d, 2H), 7.70-7.78 (m, 1H), 7.82-7.92 (m, 1H), 7.95 (s, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [CH3:1]OC1C=C(C=C(OC)C=1CC)C(Cl)=O.[C:16]([C:20]1[CH:28]=[C:27]([O:29][CH3:30])[C:23]([C:24](Cl)=[O:25])=[C:22]([O:31][CH3:32])[CH:21]=1)([O:18]C)=[O:17].C(C(CC)(C([O-])=O)C([O-])=O)C>>[C:24]([C:23]1[C:27]([O:29][CH3:30])=[CH:28][C:20]([C:16]([OH:18])=[O:17])=[CH:21][C:22]=1[O:31][CH3:32])(=[O:25])[CH3:1]
Reactant: CCc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1cc(OC)c(C(=O)Cl)c(OC)c1
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Product: COc1cc(C(=O)O)cc(OC)c1C(C)=O

Procedure:
3,5-Dimethoxy-4-ethyl-benzoyl chloride. Starting from 4-carbomethoxy-2,6-dimethoxy-benzoyl chloride and diethyl-malonate, and following the procedure described by H. G. Walker et al., in Journal Am.Chem.Soc., 68, 1387 (1946), the methyl ester of 4-acetyl-3,5-dimethoxy-benzoic acid is obtained, m.p. 100°-102°C. This compound is hydrolized under alkaline conditions to the corresponding acid. (M.p. 174°-179°C from ethanol/water). The conversion of the -COCH3 group at the position 4 to --CH2CH3 is achieved by the reductive method described by Huang Minlon in Journal Am.Chem.Soc., 68, 2487, 1946. The obtained 3,5-dimethoxy-4-ethylbenzoic acid has m.p. 190°-91°C (from methanol/water). The corresponding chloride is obtained in the same way as for the compound under A). M.p. 88°-89°C (from diethyl ether).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO.O>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)c(O)cc1O
Temperature: 55 °C
Yield: 83.4 %

Procedure:
8.9 kg of 5-bromo-2,4-dihydroxybenzoic acid are dissolved in 70 l of methanol and heated to 55° C. 800 ml of sulfuric acid (w=95-98%) are subsequently metered in, and the mixture is stirred under gentle reflux for 4 days, with a further 500 ml of sulfuric acid (w=95-98%) being added daily (3 times). The reaction mixture is stirred into a cooled solution (5° C.) of 9 kg of sodium hydrogencarbonate in 100 l of water. Filtration and drying in vacuo at 50° C. gives 7.87 kg (83%) of methyl 5-bromo-2,4-dihydroxybenzoate (white crystals), MW 247.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[F:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH2:22])=[S:21])[CH:16]=[CH:17][CH:18]=1>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:22]=[C:20]([NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)[S:21][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: NC(=S)Nc1cccc(F)c1
Product: Fc1cccc(Nc2nc(-c3ccc(Br)cc3)cs2)c1

Procedure:
The title compound is prepared analogously to Example 2-1 step B using 2-bromo-1-(4-bromophenyl)-ethanone and 3-fluorophenylthiourea: (M+H)+ 350.9.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.[CH3:35][N:36]1[CH2:41][C:40](=[O:42])[NH:39][C:38]2[CH:43]=[C:44]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4([NH:57]C(=O)OC(C)(C)C)[CH2:56][CH2:55][CH2:54]4)=[CH:49][CH:48]=3)=[N:46][C:37]1=2>>[NH2:57][C:53]1([C:50]2[CH:49]=[CH:48][C:47]([C:45]3[C:44]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:43][C:38]4[NH:39][C:40](=[O:42])[CH2:41][N:36]([CH3:35])[C:37]=4[N:46]=3)=[CH:52][CH:51]=2)[CH2:54][CH2:55][CH2:56]1
Reactant: CN1CC(=O)Nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CN1CC(=O)Nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc21
Yield: 125.7 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl 1-(4-(4-methyl-2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)phenyl)cyclobutylcarbamate (29 mg, 0.060 mmol) was reacted to afford the title compound (29 mg, 97%). LCMS (Method A): RT=3.69 min, M+2H+=386. 1H NMR (500 MHz, MeOD): 7.44 (2H, d), 7.32 (2H, d), 7.20-7.28 (3H, m), 7.12 (2H, d), 7.02 (1H, s), 4.08 (2H, s), 3.11 (3H, s), 2.70-2.80 (2H, m), 2.50-2.63 (2H, m), 2.13-2.27 (1H, m), 1.88-2.02 (1H, m).