Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[F:13][C:14]([F:22])([F:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18]>>[CH3:18][C:17]1[N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[N:3]=[C:15]([C:14]([F:22])([F:21])[F:13])[CH:16]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Cc1cc(C(F)(F)F)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 1,1,1-trifluoro-2,4-pentanedione: MS (ESI) m/z 270 [M+H]+, 1H-NMR (CDCl3) δ 7.41-7.34 (4H, m), 6.45 (1H, s), 3.93-3.86 (211, m), 2.94 (2H, t, J=6.6 Hz), 2.34 (3H, s).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1>CO>[CH3:1][O:12][C:11]([C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Yield: 81 %

Procedure:
Acetyl chloride (5 mL) was added to a 0° C. solution of methanol (40 mL) and the solution was allowed to warm to room temperature. 5-Methyl-thiophene-2-carboxylic acid (Lancaster; 1.58 g, 11.1 mmol) was added and the solution was allowed to stir at room temperature over the weekend. The solvents were evaporated under reduced pressure and ethyl acetate was added. The solution was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate) filtered and evaporated to give 5-methyl-thiophene-2-carboxylic acid methyl ester (1.40 g, 81%) as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45].O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:44]([N:43]([CH3:48])[CH3:42])(=[O:46])=[O:45])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of 224 mg (0.5 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) and 130 mg (1 mmol) of DIPEA in 10 mL of CH2Cl2 was treated with 150 mg (1 mmol) of dimethylsulfamoyl chloride and the mixture was stirred at room temperature overnight. Water was added, and the organic layer was separated and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (9:1), gave 217 mg (78% yield) of 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide: mp (MeOH) 286-288° C.; 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.7 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.96 (m, 4H), 3.89 (m, 4H), 3.78 (m, 4H), 3.34 (m, 4H), 2.87 (s, 6H); Anal. Calcd. for C22H29F2N9O4S: C, 47.7; H, 5.3; N, 22.8. Found: C, 47.95; H, 5.3; N, 22.9%.
Reaction SMILES: O[CH:2]([C:11]1(OC)[CH:16]=[CH:15][N:14]=[CH:13][CH2:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:19]([O-:22])(=O)C.[C:23]([O-])(O)=[O:24].[Na+].[NH4+].[Cl-]>O1CCCC1.CN(C=O)C>[CH3:23][O:24][C:8]1[CH:7]=[C:6]2[C:5]([C:3](=[O:4])[CH:2]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[CH2:19][O:22]2)=[CH:10][CH:9]=1
Reactant: COC1(C(O)C(=O)c2ccccc2)C=CN=CC1
Reactant: CC(=O)[O-]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OCC(c1ccncc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-2-(4-pyridyl)acetophenone (3.51 g, 14.4 mmol) in tetrahydrofuran (30 ml) were added under ice-cooling dry acetate (2.72 ml, 28.8 mmol) and a solution of N,N,N′,N′-tetramethyl-diaminomethane (1.96 ml, 14.4 mmol) in DMF (10 ml), which was then stirred for 30 minutes. After the reaction was completed, the reaction solution was neutralized under ice-cooling using saturated aqueous NaHCO3 solution, extracted with ethyl acetate, and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mg), tetta-n-butylammonium fluoride (11.0 mmol/g, 0.144 mg, 0.144 mmol) was added thereto under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated aqueous NH4Cl solution was added to the reaction solution, which was then extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give 7-methoxy-3-(4-pyridyl)chroman-4-one (2.02 g, yield 55%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Br>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:28][CH:30]2[O:32][CH2:31]2)[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC1CO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
A mixture comprising 2 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 20 ml of dimethylformamide, 1.4 g of potassium carbonate and 1.4 g of epibromohydrin, was stirred at 60° C. overnight. After distilling off the solvent under reduced pressure, the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed sequentially with an aqueous potassium carbonate solution and with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 2.6 g of the above-identified compound as oily substance.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 89 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 89% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.81 (m, 1H), 2.03 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.33 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.93 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][CH:8]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[O:1]([CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cnc(Nc2ccccc2)nc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
5-Hydroxymethyl-2-(phenylamino)pyrimidine (280 mg, 1.39 mmol) obtained in Step 3 was dissolved in DMF (10 mL), and imidazole (190 mg, 2.76 mmol) and tert-butyldimethylsilylchloride (420 mg, 2.79 mmol) were added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 5-(tert-butyldimethylsiloxymethyl)-2-(phenylamino)pyrimidine (423 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]1([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:38]3[CH:39]=[CH:40][C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:36][CH:37]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(-c4ccccc4)cc3)C2=O)cc1
Yield: 81 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and (4-phenylphenyl)boronic acid instead of phenyl boronic acid, to obtain the title compound (81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[F:20][CH:21]([F:24])[CH2:22][NH2:23].CO>C1COCC1>[F:20][CH:21]([F:24])[CH2:22][NH:23][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: NCC(F)F
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCC(F)F)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Iodomethyl-thiazol-2-yl)-3-(3-fluorobenzyl)-urea (Intermediate 7, 1 eq.) was taken up in THF (0.3 M) and 2,2-difluoroethanamine (20 eq.) was added. The reaction was stirred overnight at ambient temperature. Some of the starting material, Intermediate 7 remained. Added additional 2,2-difluoroethanamine (10 equivalents). The reaction was complete after 2-4 hours. Removed solvent; coevaporated twice with MeOH. Crude is a 1:1 mixture of title compound and bis addition impurity. (used as is in subsequent step).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][C:13]([CH3:19])([CH3:18])[CH2:12]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)[C:15](=[O:17])[CH2:14][C:13]([CH3:19])([CH3:18])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CC(C)(C)CC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CC(C)(C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)-4,4-dimethylpiperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.14 min.; [M+H]+: 437.96 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35](=[O:36])[NH:37][CH3:38])=[CH:39][CH:40]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: CNC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (170 mg, 0.41 mmol) in 10 mL of DMF were added 4-amino-N-methyl-benzamide (81 mg, 0.54 mmol), HATU (205 mg, 0.54 mmol) and DIEA (79 mg, 0.61 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to give a solid as a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (66 mg, 29.7%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.66 (s, 1H), 10.21 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 8.59 (d, 1H, J=7.2 Hz), 8.38-8.37 (m, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.89-7.82 (m, 6H), 7.71-7.68 (m, 12H), 7.54-7.50 (m, 1H), 6.97 (d, 1H, J=8.7 Hz), 3.78 (s, 3H), 3.72 (s, 3H), 2.78 (d, 1H, J=3.9 Hz). LC-MS: 541.1 [M+H]+, tR=1.72 min. HPLC: 96.60% at 214 nm, 97.75% at 254 nm, tR=6.68 min.
Reaction SMILES: COCCOC[CH2:7][O:8][CH2:9][CH2:10][NH2:11].[CH3:12][C@@H:13]1[CH2:15][C@H:14]1[C:16](O)=O>>[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]1[CH2:15][CH:14]1[CH3:16]
Reactant: C[C@@H]1C[C@H]1C(=O)O
Reactant: COCCOCCOCCN
Product: COCCNCC1CC1C

Procedure:
Prepared from 2-[2-(2-methoxyethoxy)ethoxy]ethanamine and trans-2-methylcyclopropanecarboxylic acid using steps A and B in the procedure described for the synthesis of Intermediate 3.6.1. MS (ES, M+H) 232.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C[O-].[Na+].Cl[CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33]>C(Cl)(Cl)Cl.ClC1C=CC=CC=1.CO>[CH2:30]([N:31]([CH2:34][CH3:35])[CH2:32][CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH:10]=[C:9]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1)[CH3:29]
Reactant: O=c1cc(-c2ccccc2)n(-c2ccc(O)cc2)c2ccccc12
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)CCOc1ccc(-n2c(-c3ccccc3)cc(=O)c3ccccc32)cc1

Procedure:
By following a procedure similar to that described in Example 1 and using 49.5 g. 1-(4-hydroxyphenyl)-2-phenyl-4(1H)-quinolone, 10.5 g. sodium methoxide, 500 ml. chlorobenzene, 45 ml. dry methyl alcohol, and 26 g. N-(2-chloroethyl)diethylamine in 80 ml. chlorobenzene there was obtained on evaporation to dryness of the chloroform extract and recrystallization from isopropyl alcohol 32 g. 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-phenyl-4(1H)-quinolone; m.p. 115°-117° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2C)CC1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1O[C@H]1CC[C@H](C(=O)NN)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-o-tolyloxy-cyclohexanecarboxylic acid methyl ester (0.091 g, 0.36 mmol) and hydrazine hydrate (0.02 ml, 0.36 mmol) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was suspended in toluene. After evaporation of the solvent the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.73 g, 81%) as white solid, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH3:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1ccccc1N
Reactant: CSc1ncnc2cc(N)ncc12
Product: COc1ccccc1Nc1ncnc2cc(N)ncc12
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 46.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (227 mg, 1.18 mmole) and o-anisidine (1.00 mL, 8.87 mmol) is stirred under N2 at 180° C. for 2.5 h. The resulting product is chromatographed over silica gel (5% EtOH/EtOAc) to give 7-amino-4-(2-methoxyanilino)pyrido[4,3-d]pyrimidine (147 mg, 47%) as a yellow solid. 1H NMR (DMSO) δ 9.44 (1H, brs), 9.25 (1H, s), 8.22 (1H, s), 7.54 (1H, dd, J=7.7, 1.4 Hz), 7.24 (1H, ddd, J=8.1, 7.4, 1.5 Hz), 7.10 (1H, dd, J=8.2, 1.2 Hz), 6.98 (1H, dt, Jd=1.3 Hz, Jt=7.5 Hz), 6.52 (2H, brs), 6.41 (1H, s), 3.79 (3H, s)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[N:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+:15].[ClH:16].C1(C)C=CC=CC=1>C1COCC1>[CH3:13][O:12][C:8]1[N:9]=[C:10]([CH3:11])[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1.[Cl-:16].[Na+:15]
Reactant: Cl
Reactant: COC(=O)c1ncc(OC)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cnc(C(=O)O)c(C)n1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 105 mg (0.577 mmol) 5-methoxy-3-methyl-pyrazine-2-carboxylic acid methyl ester in 2.6 ml THF was cooled to 0. ° C., 0.635 ml (0.635 mmol) 1N sodium hydroxide was added dropwise and the mixture was stirred at room temperature for 1.5 h. After re-cooling to 0° C. 0.635 ml (0.635 mmol) 1N HCl and 1.2 ml toluene were added and the solvents were evaporated to provide the title compound together with sodium chloride as brownish solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([F:18])[CH:11]=1>C(O)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[C:12]([F:18])[CH:11]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
A solution of pyruvic acid (1.9 mL, 27.1 mmol) in ethanol (2.5 mL) was added to a 0.5 M sodium hydroxide solution (74.0 mL). The reaction mixture was stirred at room temperature for 10 minutes and then a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g, 24.6 mmol) in ethanol (22.5 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid was washed with ethyl acetate, diluted with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.5 g of the titled compound as a yellow solid.
Reaction SMILES: C(OC(NC(C1C=CC(O)=C(COC)C=1)C(O)=O)=O)C1C=CC=CC=1.C(OC(Cl)=O)C(C)C.N[CH:35]1[C:41](=[O:42])[N:40]2[CH:36]1[S:37][C:38]([CH3:47])([CH3:46])[CH:39]2[C:43]([OH:45])=[O:44].C(N(CC)CC)C>O1CCCC1.O1CCCC1.O>[CH3:46][C:38]1([CH3:47])[S:37][CH:36]2[N:40]([C:41](=[O:42])[CH2:35]2)[CH:39]1[C:43]([OH:45])=[O:44]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: COCc1cc(C(NC(=O)OCc2ccccc2)C(=O)O)ccc1O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)SC2CC(=O)N2C1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
α-(Benzyloxycarbonyl)amino-4-hydroxy-3-(methoxymethyl)benzeneacetic acid (0.1 mole) is dissolved in tetrahydrofuran (THF). The temperature of the solution is maintained at about -10° C. and 0.2 mole of isobutylchloroformate is added. After stirring for about 30 minutes at -10° C., 0.1 mole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid in a 50/50 THF/water solution containing 0.1 mole of triethylamine is added to the above formed solution. This mixture is stirred for 30 minutes at -10° C. and then the temperature is raised to about 20° C. Stirring is continued for an additional 30 minutes. The pH is adjusted to 4.5 to 5.5, and the coupled product is extracted into ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the coupled product, 6-[[(benzyloxycarbonyl)amino]-hydroxy-3-(methoxymethyl)-phenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
Reaction SMILES: N1C2C=CC=CC=2N=N1.[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26])(=[O:22])[CH3:21].CN1CCOCC1.Cl>O1CCCC1>[C:20]([NH:23][CH:24]([CH2:25][S:26][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([CH3:10])=[CH:12][CH:13]=1)[C:27]([OH:29])=[O:28])(=[O:22])[CH3:21]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)NC(CSC(=O)c1ccc(C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of benzotriazole (9.91 g, 83.2 mmol) in tetrahydrofuran (80 mL) was added 4-methylbenzoyl chloride (5.0 mL, 37.8 mmol) (5 g, 95%). After 2 hours, the resulting slurry was filtered and the solid was rinsed with tetrahydrofuran (25 mL). The filtrates were combined and added to a solution of N-acetyl-L-cysteine (5.55 g, 34.0 mmol) and N-methylmorpholine (3.74 mL, 34.0 mmol) in tetrahydrofuran (50 mL) at 0° C. The resulting mixture was allowed to warm to ambient temperature over 16 hours. Aqueous hydrochloric acid (1 M, 100 mL) was added to the mixture and the resulting mixture was concentrated at reduced pressure to a volume of approximately 125 mL. Additional aqueous hydrochloric acid (80 mL) was added and the mixture was extracted with dichloromethane (180 mL then 80 mL). The combined organic extracts were combined, dried over sodium sulfate, filtered and concentrated at reduced pressure. Ethyl acetate (100 mL) was added and the resulting slurry was stirred for 2 hours. The resulting slurry was filtered and dried to give a white solid (5.7 g, 60%). 1H NMR (300 MHz, DMSO) δ=12.94 (s, 1H), 8.34 (d, J=7.9 Hz, 1H), 7.86-7.74 (m, 2H), 7.35 (d, J=8.5 Hz, 2H), 4.43 (dt, J=5.0, 8.4 Hz, 1H), 3.53 (dd, J=5.0, 13.8 Hz, 1H), 3.21 (dd, J=8.5, 13.8 Hz, 1H), 2.37 (s, 3H), 1.83 (s, 3H). MS (ESI) m/z 282 (M+1)+.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][C:15]=3[CH:24]=2)=[O:9])=[CH:6][CH:5]=1.[ClH:27].[CH3:28]O>>[ClH:27].[NH2:1][N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH:18]([CH2:20][C:21]([O:23][CH3:28])=[O:22])[CH2:17][CH2:16][C:15]=3[CH:24]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3)ccc2O1
Reaction time: 2 h

Procedure:
A suspension of 0.35 g (1.0 mmol) of the acid from Example 48 in 20 ml methanol was cooled to 0° C. and saturated with gaseous hydrogen chloride. After 2 hours stirring it was concentrated under reduced pressure, and the remaining compound (343) was recrystallized from methanol/ether. Yield: 0.29 g (72%) of yellow crystals, m.p. 235-237° C.