Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:26]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:20]2[CH:21]=[N:22][CH:23]=[N:24][CH:25]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:39][CH:40]1[CH2:44][CH2:43][O:42][CH2:41]1)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CN(C=O)C.CCOC(C)=O>[N:22]1[CH:21]=[C:20]([C:8]2[CH:9]=[CH:10][C:11]3[O:12][C:13]4[C:18](=[CH:17][C:16]([O:19][CH2:39][CH:40]5[CH2:44][CH2:43][O:42][CH2:41]5)=[CH:15][CH:14]=4)[C@:5]4([CH2:4][O:3][C:2]([NH2:1])=[N:26]4)[C:6]=3[CH:7]=2)[CH:25]=[N:24][CH:23]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: O=S(=O)(OCC1CCOC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(OCC3CCOC3)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(S)-2-Amino-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.075 g, 0.217 mmol) and cesium carbonate (0.106 g, 0.325 mmol) were dissolved in DMF (0.7 mL) and stirred for five minutes before being cooled in an ice bath. (Tetrahydrofuran-3-yl)methyl trifluoromethanesulfonate (0.056 g, 0.238 mmol) was dissolved in DMF (0.15 mL) and added dropwise to the reaction, which was stirred for one hour. An additional equivalent of triflate was added and the reaction was stirred for five days. The reaction was cooled to 0° C. and 0.5 eq. of triflate was dissolved in 0.1 mL of DMF and added dropwise to the reaction. The reaction was stirred for two days. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM) but the material was impure so the material was repurified via Gilson HPLC (10-90% MeCN:H2O). The product fractions were partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-2′-(pyrimidin-5-yl)-7′-((tetrahydrofuran-3-yl)methoxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. LC-MS MH+ 431.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:33])[N:10]3[CH2:25][CH:24]([O:26]C(=O)C(C)(C)C)[CH2:23][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=2)=[CH:4][CH:3]=1.[C:34]1([O-:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:33])[N:10]3[CH2:25][CH:24]([OH:26])[CH2:23][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CC(O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 6-(4-fluorophenyl)-7-(2-methane-sulfonyl-pyrimidin-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-2-yl ester, 35, (50 mg, 0.105 mmol) in THF (1 mL) is slowly cannulated into a solution of sodium phenolate in THF (1 mL) at 0° C. The cooling bath is removed and the reaction stirred at room temperature for 1 hour. The reaction is quenched with NH4Cl (sat. aq.) (500 μL). The reaction mixture is concentrated in vacuo and the residue diluted taken up in ethyl acetate (15 mL). The solution is washed with water (20 mL) and a 5% aqueous Na2CO3 (20 mL). The combined aqueous layers are extracted with ethyl acetate (25 mL) and brine (20 mL), dried, filtered and concentrated in vacuo. The crude material is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 9 mg (21% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) □ 8.43 (d, J=5.2 Hz, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.31-7.27 (m, 3H), 7.19 (d, J=8.2 Hz, 2H), 7.03 (t, J=8.6 Hz 2H), 6.80 (d, J=5.2 Hz, 1H), 5.41 (br s, 1H), 4.82 (m, 1H), 4.23 (d, J=12.4 Hz, 1H), 3.95-3.85 (m, 2H), 3.76 (dd, J=12.4, 4.4 Hz, 1H); HRMS m/z calcd for C22H18FN4O3 (MH+) 405.1363, found 405.1365.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].[ClH:22].[CH:23]([NH:25][C@@H:26]1[C:31](=[O:32])[O:30][C:28](=[O:29])[CH2:27]1)=[O:24].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.CO>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:11])[OH:12])[NH2:8].[ClH:22].[CH:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:27][C:28](=[O:29])[OH:30])=[O:24]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Solvent: O
Solvent: CO
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The present invention relates to a process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride is prepared by a process comprising: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water or in water containing methanol at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture successively with hydrochloric acid in the presence of methanol without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to deposit α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccsc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.8 ml of n-pentanoic acid chloride was added to 50 ml of an anhydrous pyridine solution containing 5.0 g of methyl 3-aminothiophene-2-carboxylate at 0° C. The mixture was stirred at 0° C. for 1 hour and further stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1N chloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in this order. Ethyl acetate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (elution with n-hexane:ethyl acetate=5:1) to provide 7.0 g of methyl 3-pentanoylaminothiophene-2-carboxylate as a colorless oily compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@H:27]([C:37]3[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[OH:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-tert.-butyl-iodo-benzene.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[BH4-].[Na+]>C(O)(=O)C.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)CNc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
Pivalaldehyde (20.4 g, 236 mmol, 25.6 mL) was added to a solution of 4-chloroaniline (30.2 g, 236 mmol) in concentrated acetic acid (475 mL) at ambient temperature. After 1.5 hour, the reaction mixture was cooled to 0° C. and sodium borohydride (11.7 g, 307 mmol) was added portionwise over 15 minutes After stirring for 1 hour, the resulting mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed successively with water (3×), aqueous 2N sodium hydroxide (2×), saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 47.2 g (99%) of the title compound as an off-white solid which was taken on crude to the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18](=[O:19])[N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:25]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1CCC(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)N2CCC(c3ccccc3)CC2)cc1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.611 g) in dimethylformamide (6 mL) under argon was treated with 55% sodium hydride (0.148 g), stirred for 30 minutes in a ice-water bath and then 1-(bromoacetyl)-4-phenyl-piperidine (0.8 g) in dimethylformamide (5 mL) was added. The solution was stirred at room temperature for 18 hours and worked up as in Example 20. The crude product was purified by flash chromatography (ethyl acetate-hexane; 3:7 increasing to 2:5) to provide 0.9 g of 4-[2-oxo-2-(4-phenyl- 1-piperidinyl)ethoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: IC.[CH2:3]([O:5][C:6]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH2:26][CH3:27])=[C:12]([OH:28])[CH:11]=2)=[O:7])[CH3:4].[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH2:26][CH3:27])=[C:12]([O:28][CH3:29])[CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1oc2cc(O)c(CC)cc2c(=O)c1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1oc2cc(OC)c(CC)cc2c(=O)c1-c1ccc(F)cc1
Yield: 86.8 %

Procedure:
Iodomethane (0.10 ml, 12 equiv.) was added to a solution of 6-Ethyl-3-(4-fluoro-phenyl)-7-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (50 mg, 0.14 mmol) and potassium carbonate (58 mg, 3.0 equiv.) in acetone and the mixture refluxed overnight. The volatiles were then evaporated in vacuo and the residue partitioned between water (15 ml) and EtOAc (15 ml). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness in vacuo to give a white crystalline product (45 mg, 87% yield)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:49][CH3:50])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:48]=[C:27]([NH:26][C:7](=[O:9])[C:6]5[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=5)[CH:28]=[CH:29][C:30]=4[O:49][CH3:50])=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cccc(OC(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 50.3 %

Procedure:
Using 3-(trifluoromethoxy)benzoic acid (120 mg, 0.58 mmol), oxalyl chloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (130 mg, 54%) was obtained as a white powder.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)=O.O(Cl)Cl>>[CH:1]1[N:6]2[C:7]3[C:12]([CH:13]=[CH:14][C:5]2=[CH:4][N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=CNCc1ccc2ccccc2n1
Agent: ClOCl
Product: c1ccc2c(c1)ccc1cncn12

Procedure:
Treatment of 1.86 g. of 2-formamidomethylquinoline with 15 ml. of hosphorous oxychloride as in Preparation AIII-a gave imidazo[1,5-a]quinoline, which is used without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=[CH2:10])[C:6]=2[C:11]=1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]>C(O)C.[Pd]>[F:17][C:14]([F:15])([F:16])[C:13]([NH:12][C:11]1[C:6]2[CH:7]([CH3:10])[CH2:8][O:9][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: C=C1COc2ccc(Cl)c(NC(=O)C(F)(F)F)c21
Agent: [Pd]
Solvent: CCO
Product: CC1COc2cccc(NC(=O)C(F)(F)F)c21
Reaction time: 20 h
Yield: 104.2 %

Procedure:
A solution of Intermediate 23 (0.10 g) in ethanol (20 ml) was added to 10% palladium on carbon (0.20 g) and the mixture stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through ‘hyflo’ filter aid, washed with ethanol and the solvent removed in vacuo to give the title compound as a white solid (0.092 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc2cccnc12)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22.1 %

Procedure:
1-tert-Butoxycarbonylpiperazine (2.22 g) and triethylamine (2.0 mL) were dissolved in dichloromethane (100 mL), and 8-quinolinesulfonyl chloride (2.71 g) was added thereto. The mixture was stirred at room temperature for 14 hr. 10% citric acid solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added thereto. The mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform, and the extract was dried and concentrated under reduced pressure to give 1-(8-quinolinesulfonyl)piperazine (0.73 g) as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:48])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][C:18]([O:46][CH3:47])=[C:19]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH:20]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][C:18]([O:46][CH3:47])=[C:19]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH:20]=4)[N:15]=[C:14]([C:10]4[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=4)[O:7][CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:48])[N:23]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(OCC(=O)NC(C)C)c3)nc2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(OCC(=O)NC(C)C)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate from the previous step was taken up in CH2Cl2 (2 mL) and TFA (5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and a portion of the residue was purified by preparative HPLC (10-35-90, 10-30-90, 0-15-90, 5-20-90 and 20-40-90 methods) to give 2-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)-quinazolin-2-yl)phenoxy)-N-isopropylacetamide (0.039 g, 68.4 μmol). MS 557 (M+1). HPLC retention time 5.48 mins.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[OH:36])(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1([CH3:71])[CH:61]=[CH:60][C:59]([S:62]([O:65][CH2:66][CH2:67][CH:68]([CH3:70])O)(=[O:64])=[O:63])=[CH:58][CH:57]=1>O1CCCC1>[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH:68]([CH3:70])[CH2:67][CH2:66][O:65][S:62]([C:59]1[CH:58]=[CH:57][C:56]([CH3:71])=[CH:61][CH:60]=1)(=[O:63])=[O:64])(=[O:17])[CH3:16]
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC(C)CCOS(=O)(=O)c2ccc(C)cc2)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reaction time: 4 h
Yield: 36.9 %

Procedure:
A solution of diisopropyl azodicarboxylate (1.54 g, 7.61 mmol) in anhydrous tetrahydrofuran (10 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)benzothiazoline (2.56 g, 7.62 mmol), triphenylphosphine (2.00 g, 7.61 mmol) and 3-p-toluenesulfonyloxy-1-methylpropanol (1.86 g, 7.61 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for four hours. The reaction mixture was concentrated, and the obtained oily matter was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=4/1) to give 1.58 g (37%) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]([CH3:33])=[CH2:32]>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:32][C:31]([CH3:33])=[CH2:30])[CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(O)cc32)cc1O
Reactant: C=C(C)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CN1CCc2cc(OC)c(O)cc2C1Cc1ccc(OC)c(O)c1
Reaction time: 3 h

Procedure:
5.7 g. (18.07 mmol) (-)-7-Hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 3.7 g. (44 mmol) sodium bicarbonate in 120 ml. ethanol are mixed with 1.76 ml. (1.64 g., 18,07 mmol) 3-chloro-2-methylprop-1-ene. The mixture is allowed to react for 30 minutes at ambient temperature and thereafter for 3 hours at 80° C., while stirring. The usual working up and chromatographic purification on silica gel with chloroform as elution agent gives (+)-7-hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-2-(2-methylprop-2-enyl)-1,2,3,4-tetrahydroisoquinoline in the form of a TLC-uniform yellowish foam.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17]Br)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][O:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccc(Br)nc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.50 g), tert-butyl(2-bromoethyl)carbamate (2.32 g), cesium carbonate (3.65) and N,N-dimethylformamide (30 mL) was stirred at 40° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.47 g).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:11][N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[S:18][CH:17]=[N:16][C:15]=1[C:14]1[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:13]=1
Reactant: COc1ccc(CNc2ncc(-c3cccnc3)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cccnc2)cc1-c1ncsc1-c1cccc(Cl)c1Cl
Yield: 9 %

Procedure:
A solution of N-(4-methoxybenzyl)-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)-5-(pyridin-3-yl)pyridin-2-amine (24 mg, 0.046 mmol) in TFA (1 mL) was heated to reflux overnight. The solvent was removed in vacuo and the compound was purified by reversed-phase HPLC to provide 3-(5-(2,3-dichlorophenyl)thiazol-4-yl)-5-(pyridin-3-yl)pyridin-2-amine as a while solid [2.2 mg, 9% yield; LC-MS M+H=399.2; 1H-NMR (300 MHz, methanol-d4) 9.34 (1H, s), 8.57 (1H, dd), 8.41 (1H, d), 8.28 (1H, d), 7.79 (1H, d), 7.71 (1H, dd), 7.58 (1H, dd), 7.57 (1H, t), 7.46 (1H, t), 2.64 (3H, s)].
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[O:6]>>[Cl:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:2])=[O:6]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)C(Cl)c1ccccc1

Procedure:
To 150 ml. of concentrated ammonium hydroxide and 75 g. of ice was added 20 g. of 2-chloro-2-phenylacetylchloride. The amide formed immediately. The reaction mixture was stirred for 30 minutes and the white solid precipitate which was collected weighed 16.9 g. This precipitate was dissolved in 100 ml. of hot ethyl acetate and then diluted with petroleum ether, after which there was collected 14.3 g. of white cottony needles having an m.p. of 120°-121° C.