Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH3:7])[CH3:6].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:24](O)=[O:25])=[CH:18][CH:17]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:31]([O:30][C:28]([NH:27][C@H:23]([C:24]([NH:2][CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:5]([CH3:7])[CH3:6])=[O:25])[CH2:22][C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1)=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)[C@@H](CN)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The (2S)-1-amino-2-tert-butyloxycarbonylamino-3-methylbutane hydrochloride was obtained from tert-butyloxycarbonyl-L-valinol in accordance with the literature procedures (Mattingly, P. G., Synthesis, 1990, 1990, 366-368. Desired Boc-protected alcohol was obtained from Boc-L-valine, in accordance with the literature procedure (Juszczyk, P. et al., Letters In Peptide Science. 2003, 10, 79-82). The solution of (2S)-1-amino-2-tert-butyloxycarbonylamino-3-methylbutane hydrochloride (0.50 g, 2.096 mmol), Z-L-phenylalanine (0.659 g, 2.20 mmol), triethylamine (611 μl, 4.4 mmol) and HOBt (0.297 g. 2.20 mmol) in 10 ml of DMF was cooled on ice bath and DCC (0.498 g, 2.42 mmol) was added in small portions, during 0.5 h. The stirring was continued during 1 hour, next the reaction mixture was left in room temperature overnight. The precipitated DCU was filtered off, washed with DMF (2×3 ml) and the combined filtrates were evaporated under reduced pressure. The solid residue was dissolved in ethyl acetate (200 ml) and the solution was washed with 1 M hydrochloric acid (3×70 ml),
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl>[CH3:19][O:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:23]
Reactant: COC(=O)c1ccccc1N
Reactant: COCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccccc1C(=O)OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 3.02 g (20 mmol) of methyl anthranilate in 30 ml of methylene chloride was added 2.22 g (22 mmol) of triethylamine. Into the mixture, a solution of 2.39 g (22 mmol) of methoxyacetyl chloride in 15 ml of methylene chloride was dropwise added under chilling with ice. The resulting mixture was then stirred for 1 hour. After adding ice, the stirred mixture was made alkaline by addition of 1 N aqueous sodium hydroxide and then extracted with chloroform. The organic portion was collected and washed sequentially with 3 N HCl, 6 N HCl, water and saturated aqueous sodium chloride. The washed chloroform portion was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.6 g of the desired compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[O:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCC1(C2CCCC2)CC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC1(C2CCCC2)CC(=O)CC(=O)O1

Procedure:
A solution of [2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.8 mmol) from Step 4 above in 10% TFA/CH2Cl2 was stirred at room temperature for 20 minutes. The reaction was concentrated by rotary evaporation and used as is without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=O.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19].C(O)C>>[C:18]([N:22]1[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(O)cc1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Product: CC(C)(C)n1nc(C(F)(F)F)cc1-c1ccc(O)cc1
Temperature: 150 °C
Yield: 63.3 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-hydroxyphenyl)butane-1,3-dione (500 mg, 0.002 mol) and tert-butylhydrazine hydrochloride (270 mg, 0.0022 mol) in ethanol (12 mL, 0.21 mol) was heated at 150° C. in microwave for 1 h. Solvent was removed and the residue was purified via automated flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give the product as an off-white solid (0.36 g, 60%). LCMS Rt=1.75 minutes
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH3:16][C:17]1([CH3:23])[NH:21][C:20](=O)[CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:20]3[CH2:19][CH2:18][C:17]([CH3:23])([CH3:16])[N:21]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1(C)CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccc(Cl)cc32)=N1

Procedure:
Reaction of 2-chlorophenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides 2-CHLORO-10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 118°-120° C., from ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:9][CH:10]=[N:11][CH:12]=2)=[CH:3][CH:2]=1.Cl.[C:32](N)(=N)C>>[CH3:32][C:10]1[N:9]=[C:8]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:12][N:11]=1
Reactant: CC(=N)N
Reactant: c1ccc2nc(COc3ccc(-c4ncncc4-c4ccncc4)cc3)ccc2c1
Agent: Cl
Product: Cc1ncc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline but substituting acetamidine hydrochloride provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.63 (S, 1H), 8.58(m, 2 H), 8.17 (d, J=8.7 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1 H), 7.70 (m, 1 H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.37 (m, 2H) 7.15 (d, J=6.2, 2H), 6.93 (d, J=9.1 Hz, 2H), 5.35 (s, 2H); MS: (M+H m/z=405.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21](O)[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20].CN(C)C=O.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([Cl:31])[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20]
Reactant: Cc1c(Cl)cc(C(C)O)c2c1CN(C(=O)OC(C)(C)C)CCO2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(C)Cl)c2c1CN(C(=O)OC(C)(C)C)CCO2
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 7-chloro-9-(1-hydroxyethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (280 mg, 0.82 mmol) and N,N-dimethylformamide (30 μL) in methylene chloride (6 mL) was stirred and thionyl chloride (120 μL, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 20 minutes. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired product (295 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([C@@H:12]2[O:26][C@H:25]([CH2:27][O:28]C(C3C(C)=CC=CC=3)=O)[C@@H:14]([O:15]C(C3C(C)=CC=CC=3)=O)[CH2:13]2)[C:4](=[O:38])[N:3]=1.C[O-].[Na+]>CC(O)=O>[NH2:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([C@@H:12]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[CH2:13]2)[C:4](=[O:38])[N:3]=1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2c(=O)nc(N)c3nccnc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)c2nccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 0.51 g (1 mmole) of 4-amino-1-(2-deoxy-3,5-di-O-toluoyl-β-D-ribofuranosyl)-pteridine-2-one (31) is added 50 mL of 0.0005N sodium methoxide. The mixture is stirred at room temperature for 24 h. The mixture is then neutralized with AcOH, evaporated to dryness, and twice coevaporated with H2O. The residue is then recrystallized from 50 mL of ethanol to give 32.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].N[C@H:28]1[C@@H](C)OC2C=CC=CC=2NC1=O>>[C:5]([O:4][C:3](=[O:9])[N:2]([CH3:1])[C@H:10]([C:11](=[O:25])[NH:12][C@@H:13]1[C:14](=[O:24])[NH:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[O:18][C@@H:19]1[CH3:28])[CH3:26])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@H]1Oc2ccccc2NC(=O)[C@H]1N
Product: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
In a similar manner to that described for the preparation of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate except the mixture was stirred 1.5 h and the crude product purified by silica gel chromatography, (2R,3S)-3-amino-2-methyl-2,3-dihydrobenzo[b][1,4]-oxazepin-4 (5H)-one (420 mg, 2.19 mmol) was converted to the title compound (505 mg, 61%) as a white foam.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][CH2:3][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1
Reactant: CNC(=O)c1cc2ccccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2s1
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To a stirred suspension of N-methyl benzothiophene-2-carboxamide (10.0 g, 52 mmole) in dry THF (75 mL) under argon was added a solution of 1.0 M LiAlH4 in THF (135 mL, 135 mmole) over 15 minutes. The reaction quickly became clear and was heated at reflux for 2 days. After cooling to 0° C. the reaction was carefully quenched with the sequential addition of H2O (5.1 mL), 15% NaOH in H2O (5.1 mL), and H2O (15.3 mL). The mixture was filtered through a pad of Celite® and the filter pad was rinsed with Et2O (50 mL). The filtrate was concentrated to afford the title compound (9.11 g, 99%) as a pale yellow oil which solidified in the freezer 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.3 Hz, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.33 (m, 2H), 7.17 (s, 1H), 4.06 (s, 2H), 2.53 (s, 3H), 1.56 (brs, 1H).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]([C:20]([O:22][CH3:23])=[O:21])[CH2:12]2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([CH:13]1[C:14](=[O:19])[NH:15][C:16]2[N:17]=[CH:18][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10][C:11]=2[CH2:12]1)=[O:21]
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reaction time: 2 h
Yield: 107.8 %

Procedure:
To a solution of methyl 6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (115 mg, 0.346 mmol; which may be prepared as described in Step 3) in DCM (693 μL) at 0° C. under Argon was added TFA (693 μL). The reaction was allowed to come back to room temperature under stirring for 2 h and then concentrated under vacuo to give the title compound (103 mg, quantitative) as a brown solid. The product was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)C>C(O)C.O>[C@@H:2]1([N:1]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: N[C@H]1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCN([C@H]2CCc3ccccc32)CC1

Procedure:
(S)-1-Aminoindane (37 mmol) was dissolved in ethanol (65 ml). Potassium carbonate (3.7 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (56 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 30 mil. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) yielded the desired product as an oil. 7.1 g (90%) of (S)-1-indan-1-yl-piperidine-4-one, MS: m/e=216.4 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([O:21][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:22][CH3:23])=[CH:11][CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OC)cc1
Solvent: c1ccncc1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(OC(C)=O)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-(4-Diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl alcohol (14.14 g) was dissolved in pyridine (280 ml), added with acetic anhydride (140 ml) with ice cooling and stirred at room temperature for 15 hours. After the reaction mixture was added with methanol (140 ml) with ice cooling and stirred at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to obtain 1-(4-diethylcarbamoylphenyl)-1-(2-methoxyphenyl)methyl acetate.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[O:17])[O:15][C:13](=O)[C:12]3=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[O:17])[N:20]([CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[C:13](=[O:15])[C:12]3=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C1OC(=O)c2cc(C#Cc3ccccc3)ccc21
Solvent: C1CCOC1
Product: CCO[Si](CCCN1C(=O)c2ccc(C#Cc3ccccc3)cc2C1=O)(OCC)OCC
Reaction time: 0.08 h

Procedure:
4-phenylethynyl-N [3-triethoxysilylpropyl] phthalimide was synthesized as follows. 4-phenylethynyl phthalic anhydride (PEPA) was added to a round bottom flask containing sufficient tetrahydrafuran (THF) to dissolve the PEPA. An equimolar amount of 3-aminopropytriethoxy silane (3-APS) was added to the mixture at room temperature. The mixture was then heated over a steam bath until the THF mixture began to boil (T=65° C.). The heating continued for approximately 5 minutes. The solution was then removed from the steam bath and allowed to cool. The solvent was removed using a rotovaporator at 40° C. The resulting product is a thick, viscous, yellow (amber) liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:15]([O:17]CC)=[O:16])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:15]([OH:17])=[O:16])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccn1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccccn1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
350 mg (purity 65%, 0.51 mmol) of ethyl 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 240 mg (purity 80%, 90% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[NH:21][N:20]=[C:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28].O.[OH-].[Li+].Cl>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[NH:21][N:20]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28]
Reactant: COC(=O)Cc1cc(Nc2ncnc3cc(OCCCCl)c(OC)cc23)[nH]n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(Nc3cc(CC(=O)O)n[nH]3)ncnc2cc1OCCCCl
Yield: 74.4 %

Procedure:
Methyl (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetate (100 mg, 0.247 mmol) in tetrahydrofuran (1.2 ml)/water (0.6 ml), was stirred with lithium hydroxide (21 mg, 0.493 mmol) at ambient temperature for 18 hours. The mixture was acidified with 6.0 N hydrochloric acid to pH 4 and the solid was recovered by filtration, washed with water and dried to yield (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetic acid (72 mg, 75% yield) as a beige solid:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH3:36])=[CH:34][N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[C:35]([CH3:36])=[CH:34][N:33]=[C:32]([CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)c(C)cn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M122) (0.24 g, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (110 mg, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:15])=[N:12][C:13]=1[Cl:14])[CH3:6])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:13]([Cl:14])=[N:12][C:11]([Cl:15])=[N:10][C:9]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:6])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of (R)-2-(2,4,6-trichloro-pyrimidin-5-yloxy)-propionic acid ethyl ester (522 mg, 1.74 mmol), morpholine (152 μL, 1.74 mmol) and triethylamine (484 μL, 3.48 mmol) in ethanol (15 mL) was stirred at RT for 18 hours then partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording (R)-2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propionic acid ethyl ester (490 mg, 80%). LCMS: RT=3.57 min, [M+H]+=350/352.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2
Reactant: COc1ccccc1B(O)O
Reactant: Oc1cc(Cl)cc2cc(Cl)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1cc(Cl)cc2cc(Cl)ccc12
Yield: 38 %

Procedure:
A solution of 3,6-dichloronaphthalen-1-ol (1.0 equiv), 2-methoxyphenylboronic acid (1.5 equiv), Cu(OAc)2 (1.3 equiv), pyridine (5.0 equiv), and 4 Å MS in dry DCM (3.0 mL) was stirred at room temperature for 48 h. The reaction was filtered, concentrated by rotary evaporation, and purified by column chromatography to give 3,6-dichloro-1-(2-methoxyphenoxy)naphthalene (25) (38%). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=12.0 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 7.44 (dd, J=12.0, 4.0 Hz, 1H), 7.40 (s, 1H), 7.10-7.06 (m, 2H), 7.02 (dd, J=3.4, 1.2 Hz, 1H), 6.96 (d, J=1.2 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 3.80 (s, 3H), GC-MS (ES) for C17H12Cl2O2 [M]+ 318.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C:6](=[O:21])[C@@:7]([F:20])([CH3:19])[CH2:8]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4]>CCOCC.[Cu](I)I>[CH2:3]([O:5][C:6](=[O:21])[C@:7]([F:20])([CH3:19])[CH2:8][CH3:1])[CH3:4]
Reactant: CCOC(=O)[C@](C)(F)CS(=O)(=O)c1ccc(C)cc1
Reactant: [Li]C
Agent: I[Cu]I
Solvent: CCOCC
Product: CCOC(=O)[C@@](C)(F)CC
Reaction time: 10 h

Procedure:
4.8 g (0.025 mol) of copper iodide was added to 10 ml of dried ether, which was cooled to -25°~-30° C. under a nitrogen gas flow and thereafter 36 ml of methyl lithium was added dropwise thereto. Then, 3.8 g (0.01 mol) of (S)-(-)-3-(p-toluenesulfonyl)-2-fluoro-2-methylpropionic acid monoethyl ester dissolved in 10 ml of dried ether at -15°~-20° C. was added dropwise thereto, which was stirred at 0°~5° C. for 10 hours. After the completion of the reaction, the precipitate was removed by filtration and then the filtrate was washed with 1 normal hydrochloric acid and further with water and dried on anhydrous magnesium sulfate. After the removal of magnesium sulfate by filtration, the solvent was distilled off and the residue as it is was used for the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21](=[NH:24])OC)[CH:16]=2)[NH:11][N:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21](=[NH:24])[N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: C1COCCN1
Reactant: COC(=N)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=N)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A solution of methyl 3-(3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzimidate from Step in MeOH (1.0 mL) was added morpholine (15.3 mg, 0.176 mmol) and triethylamine (90 mg, 0.88 mmol), the mixture was stirred at room temperature for 3 days. The solvent was then removed and the crude product purified by reverse phase HPLC to afford C-{3-[3-(2-Methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-C-morpholin-4-yl-methyleneamine (3.7 mg, 10% yield two steps) as a white solid. 1H-NMR (500 MHz, CD3OD) δ 8.86 (d, 2 Hz, 1H), 8.45 (d, 2 Hz, 1H), 8.37 (br s, 1H), 8.02 (m, 1H), 7.96 (t, 1.8 Hz, 1H), 7.76 (t, 7.8 Hz, 1H), 7.66 (dd, 1.8 Hz, 7.8 Hz, 1H), 7.63 (m, 1H), 7.49 (m, 1H), 7.21 (d, 8 Hz, 1H), 7.12 (dt, 1 Hz, 7.8 Hz, 1H), 3.95 (m, 2H), 3.88 (s, 3H), 3.82 (m, 2H) 3.78 (m, 2H), 3.59 (m, 2H). MS: m/z 414.1 [MH+].