Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([NH:26][C:27](=[O:43])[CH:28]=[CH:29][CH2:30][N:31]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH2:32][CH2:33][OH:34])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([NH:26][C:27](=[O:43])[CH:28]=[CH:29][CH2:30][N:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:32][CH2:33][OH:34])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCO)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCO)CC(=O)O
Reaction time: 24 h

Procedure:
1 ml of trifluoroacetic acid is added dropwise within two minutes to a solution of 330 mg of 4-[(3-bromophenyl)amino]-6-[(4-{N-[(tert-butyloxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline in 4 ml of methylene chloride while cooling with an ice bath. The reaction mixture is stirred for half an hour while cooling with an ice bath and then for a further 24 hours at ambient temperature. For working up, the mixture is evaporated to dryness in the rotary evaporator. The crude product is stirred with ethyl acetate, the solid precipitate is filtered off, washed with ethyl acetate and dried in vacuo at 50° C. Yield: 169 mg (57% of theory), Rf value: 0.50 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroactic acid=50:50:1) Mass spectrum (ESI−): m/z=528, 530 [M−H]−
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: Nc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccncc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.10 mL, 0.57 mmol) and 4-aminopyridine (76 mg, 0.59 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (39 mg, 28% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[CH:38][C:37]([C:40]([OH:42])=O)=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)[CH3:26].CCN(C(C)C)C(C)C.[F:52][C:53]([F:66])([F:65])[C:54]1[NH:55][C:56]2[C:61]([CH:62]=1)=[CH:60][C:59]([CH2:63][NH2:64])=[CH:58][CH:57]=2>CN(C=O)C>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[CH:38][C:37]([C:40]([NH:64][CH2:63][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[NH:55][C:54]([C:53]([F:66])([F:52])[F:65])=[CH:62]4)=[O:42])=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)[CH3:26]
Reactant: CCOc1cccc(-c2ccc(C(=O)O)cn2)c1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
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: CCOc1cccc(-c2ccc(C(=O)NCc3ccc4[nH]c(C(F)(F)F)cc4c3)cn2)c1
Reaction time: 24 h
Yield: 64 %

Procedure:
To a stirred solution of HATU (72.8 mg, 0.192 mmol) in DMF (1 ml) was added 6-[3-(ethyloxy)phenyl]-3-pyridinecarboxylic acid (Intermediate 6, 29 mg, 0.119 mmol) in DMF (0.5 ml), followed by DIPEA (0.050 ml, 0.287 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 24 mg, 0.096 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge. The organic layer was evaporated to dryness and purified using MDAP to give the title compound as a white solid (27 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[C:24](Cl)(Cl)=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][C:24]([OH:25])=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnc(O)o2)cc2[nH]cnc2c1F
Temperature: 25 °C
Yield: 99 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in PhMe (2 mL) and a 20% phosgene solution in PhMe (0.24 mL, 0.45 mmol) is added. The reaction mixture is stirred at reflux under N2 for 1 hour and then cooled to room temperature. The reaction mixture is quenched by the addition of a 1:1 mixture of THF and 10% HCl (20 mL). The layers are separated and the aqueous layer is extracted with THF (3×). The combined organic layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 54 mg (99%) of desired product as a yellow solid: LC/MS ESI (+) m/z 360, 362 (M+Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.83 (s, 1H), 7.88 (s, 1H), 7.30 (s, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.38 (dd, 1H), 2.30 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23].[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:31]=[C:30]1[CH2:42][C:43]([O-])=[O:44].[Na+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:43](=[O:44])[CH2:42][C:30]2[N:29]([CH3:28])[C:34](=[O:35])[CH:33]=[C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(Cl)c2)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
120 ml of pyridine, 182 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 210 mg of 3-chloro-4-fluoroaniline are added to a solution of 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 2.5 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature overnight and is then concentrated under reduced pressure. Water is added, followed by extraction with ethyl acetate, further washing with water, and concentration under reduced pressure. The residue obtained is washed with ethyl acetate and then rinsed with ethyl ether. 76 mg of N-(3-chloro-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a violet solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([CH2:6][C:7](=O)[CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[N+:16]=[N-:17].[O-]CC.[Na+].O>C(O)C>[CH:1]1([CH2:6][C:7]2[N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)[N:16]=[N:17][C:8]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CC(=O)CC1CCCC1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
Ethyl 4-cyclopentyl-3-oxobutyrate (0.781 g, 3.94 mmol, 1.25 eq.) obtained in Example 103a) and 4-azido-N-ethylbenzamide (0.60 g, 3.15 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (298 mg, 3.94 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 12 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate (35 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-yellow powder (971 mg, 2.84 mmol, 90.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:14])[C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[I-].[K+].Cl[CH2:18][CH2:19][CH2:20][C:21]#[CH:22].[OH-].[K+]>C(#N)C>[CH3:14][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([CH3:1])[C:12]=1[O:13][CH2:22][CH2:21][CH2:20][C:19]#[CH:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C#CCCCCl
Reactant: CCOC(=O)c1cc(C)c(O)c(C)c1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: C#CCCCOc1c(C)cc(C(=O)OCC)cc1C
Yield: 86 %

Procedure:
A suspension of 6.42 g ethyl 3,5-dimethyl-4-hydroxybenzoate, 5.5 g potassium iodide, 3.7 g 1-chloro-4-pentyne and 2.3 g powdered potassium hydroxide in 650 ml acetonitrile was heated at reflux under nitrogen for 16 hrs. The mixture was filtered, concentrated in vacuo and subjected to flash filtration (silica gel, 4:1 hexane/ethyl acetate) to give 7.4 g ethyl 3,5-dimethyl-4-(3-ethynylpropoxy)benzoate as a yellow oil.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[N:13]=[CH:14][S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:12]2[N:13]=[CH:14][S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2scnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2scnc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 156.3 %

Procedure:
Boron tribromide (3.09 ml, 1M solution in DCM, 3.09 mmol) was added dropwise at 0° C. to a stirred solution of 4-methoxy-benzothiazole (510 mg, 3.09 mmol) in dry DCM (30 ml). The resulting solution was warmed to 40° C. and allowed to stir overnight. The resulting solution was concentrated in vacuo and diluted with water and HCl (2N). The aqueous phase was neutralised to pH ˜7 with NaHCO3 and the solution extracted with EtOAc (3×100 ml) and the combined organic extracts dried (MgSO4) and the solvent removed in vacuo. The resulting oil was purified by flash chromatography eluting silica gel with hexane:EtOAc [4:1] to hexane:EtOAc [7:3] to give the title compound as a tan solid (730 mg, 80%); δH (300 MHz, CDCl3) 7.59 (1H, s, CH), 7.46 (1H, dd, Ar), 7.36 (1H, t, Ar), 7.02 (1H, dd, Ar).
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][C:32]([N:35]5[C@@H:39]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[CH2:38][O:37][C:36]5=[O:46])=[N:31][C:30]=34)=[CH:22][C:21]=2[F:47])=[N:16]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][C:32]([N:35]5[C@@H:39]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[CH2:38][O:37][C:36]5=[O:46])=[N:31][C:30]=34)=[CH:22][C:21]=2[F:47])=[N:16]1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccn5)nc34)cc2F)n1)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4ncn(COP(=O)(O)O)n4)c(F)c3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a stirred solution of (S)-di-tert-butyl (3-(2-fluoro-4-(5-(2-oxo-4-(pyridin-2-yl)oxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl phosphate (50 mg, 0.075 mmol) in DCM (0.5 mL) cooled to 0° C. was added TFA (0.1 mL) and the reaction stirred at 0° C. for 1 hour. The reaction was concentrated under vacuum and azeotroped with DCM/Hexanes. The remaining material was taken up in water. The aqueous layer was made basic (pH 9) by the addition of saturated NaHCO3. HCl (0.1 N) was then slowly added to the solution to adjust the pH to 2. The precipitated solid was collected by filtration, washed with acetone and diethyl ether, and dried under vacuum to give (S)-(3-(2-fluoro-4-(5-(2-oxo-4-(pyridin-2-yl)oxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl dihydrogen phosphate (22 mg, 53% yield) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=7.6 Hz, 1H), 8.79 (s, 1H), 8.73 (s, 1H), 8.52 (d, J=4.0 Hz, 1H), 7.99 (m, 2H), 7.84 (t, J=7.6 Hz, 1H), 7.72 (m, 3H), 7.31 (t, J=6.4 Hz, 1H), 6.06 (d, J=6.0 Hz, 1H), 5.95 (d, J=10.8 Hz, 2H), 4.91 (t, J=8.4 Hz, 1H), 4.32 (dd, J=8.4 Hz, 2.8 Hz, 1H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].O>CO>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH:20][NH2:21])=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of (±)-methyl 1-benzoyl-4-piperidinecarboxylate (502 mg, 2.03 mmol) in MeOH (10 mL) was added hydrazine hydrate (1.6 mL). After stirring for 24 h at rt, the reaction mixture and water (40 mL) was added. After washing with Et2O (2×20 mL), the aqueous layer was evaporated off under vacuo. The title compound was obtained as an amorphous beige solid (469 mg, 93%) in a 91.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=O)[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[O:20])[CH:2]=[CH:1][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 2-acetylnaphthalene and 4-chlorobenzaldehyde, 1-(4-chlorophenyl)-3-(2-naphthalenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH2:29])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:29][C:30]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:36])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)O
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of amine 72 (513 mg, 1.23 mmol) in CH2Cl2 (6.2 mL) was added succinic anhydride (135 mg, 1.35 mmol) and DMAP (8 mg, 0.062 mmol). The mixture was stirred for 6 h 15 min and concentrated to dryness. The crude product was purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 50-100% EtOAc in CH2Cl2 as eluent to yield acid 73 (407 mg, 64%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 27H), 1.97-2.01 (m, 6H), 2.23-2.26 (m, 6H), 2.47-2.51 (m, 2H), 2.65-2.68 (m, 2H), 6.83 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C-:14]#[N:15].[Na+].O>CS(C)=O>[CH3:13][O:12][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=1
Reactant: [C-]#N
Reactant: COc1cc(CCl)cc2c1OCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CC#N)cc2c1OCO2
Reaction time: 3 h
Yield: 60.2 %

Procedure:
To a solution of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10.2 g, 40 mmol) in DMSO (100 mL) was added NaCN (2.43 g, 50 mmol) at room temperature. The mixture was stirred for 3 h and poured into water (500 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give the crude product, which was washed with ether to afford 2-(7-methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile (4.6 g, 45%). 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 2H), 5.98 (s, 2H), 3.91 (s, 3H), 3.65 (s, 2H). 13C NMR (400 MHz, CDCl3) δ 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>O1CCOCC1.O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)CCCl
Reactant: NC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCOc1ccccc1C(N)=O
Temperature: 85 °C
Yield: 60.7 %

Procedure:
A solution of 2-hydroxy-benzamide (10 g) and potassium carbonate (35.4 g) in dioxane (50 ml) and water (4.5 ml) was added with N,N-dimethyl-2-chlorethylamine hydrochloride (6.5 g). The mixture was heated at 85° C. for 3 hours. The solvent was evaporated off, the resulting residue was poured into 5% HCI and extracted with diethyl ether. The aqueous phase was adjusted to pH with sodium bicarbonate, then extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to give the title compound as a white solid (5.7 g).
Reaction SMILES: [SH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=O.[CH:15](=[N:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:22]1[C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:1][CH:15]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCCCCCC(S)C(=O)O
Reactant: CN(C)CCN=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Reaction time: 2 h
Yield: 89.6 %

Procedure:
2-Mercaptoundecanoic acid (2 g, 9.16 mmol) and N-nicotinylidene-N',N'-dimethylethylenediamine (1.62 g, 9.16 mmol) were dissolved in toluene (50 ml), and subjected to azeotropic dehydration for 2 hours. The solvent was removed from the product mixture by evaporation under reduced pressure. The residue was purified by column chromatography, giving 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (3.1 g, 90% yield). IR (CHCl3) [cm-1 ]; 2850, 1660, 1577, 1408.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:6])C.P([O-])(O)(O)=O.[Na+]>CO>[CH3:2][O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:6]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCc1c(C(=O)OC)ncc2[nH]c3ccccc3c12
Yield: 94.7 %

Procedure:
30 mg of sodium is dissolved in 15 ml of absolute methanol. Then, 300 mg of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester is added and the mixture is heated with reflux for 2 h. The cooled solution is poured into a sodium dihydrogen phosphate solution and extracted with ethyl acetate. Crystallization in hexane/methylene-chloride yields 270 mg of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-methylester with a m.p. 134°-135° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(Cc1cccnc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CCN(Cc1cccnc1)C(=O)CCOCCc1ccccc1

Procedure:
N-(2,2-Diethoxyethyl)-3-phenethyloxy-N-(3-pyridylmethyl)propanamide (Example 5a), 0.086 g) was dissolved in anhydrous dioxane (3 mL) and treated with concentrated hydrochloric acid (0.6 mL) at ambient temperature. The resultant solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was then poured into dichloromethane (10 mL) and basified with saturated sodium bicarbonate. The organic layer was isolated, washed with water (2×10 mL), washed with brine (10 mL), dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound that was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:25]([CH3:41])([CH3:40])[CH2:26][NH:27][S:28]([CH2:31][CH2:32]N3CCN(C)CC3)(=[O:30])=[O:29])[NH:17][C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[OH:42]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:25]([CH3:41])([CH3:40])[CH2:26][NH:27][S:28]([CH2:31][CH2:32][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:30])=[O:29])[NH:17][C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[OH:42]
Reactant: CN1CCN(CCS(=O)(=O)NCC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Reactant: C1COCCN1
Product: CC(C)(CNS(=O)(=O)CCN1CCOCC1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1

Procedure:
The title compound was prepared from morpholine and the product of Example 42 Step 1 using the method described in Example 42 Steps 2 and 2; MS(ES+) m/e 520/522 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:31][CH2:32][CH2:33][CH2:34][O:23][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([C:14]2[O:13][C:11]3[N:12]=[C:7]([CH2:6][C:5]4[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[C:10]=3[N:15]=2)=[CH:21][C:20]=1[CH3:22]
Reactant: BrCCCBr
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCCBr)c(C)c3)nc12
Temperature: 60 °C
Yield: 59.6 %

Procedure:
A mixture of 300 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol (example 17), 286 mg of 1,3-dibromopropane and 98 mg of potassium carbonate in 10 ml of dimethylformamide was heated to 60° C. for 3 h. After cooling to room temperature, the solids were removed by filtration. The solvent was distilled off in vacuo and the residue was purified by chromatography (method SC1) to yield 230 mg of the title compound.