Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](Cl)(C)(C)C.BrCCBr.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:23]1[CH:24]=[C:25]([N:34]([CH2:41][CH3:42])[CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:26]([CH3:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29].C(Cl)Cl.[NH4+].[Cl-]>CC(N(C)C)=O.[Zn].[Cu]I>[CH2:41]([N:34]([CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)[C:25]1[CH:24]=[C:23]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[C:26]=1[CH3:33])[CH3:42]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: BrCCBr
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 65 °C
Yield: 63.6 %

Procedure:
To a dry flask was added zinc dust (40 mg, 0.61 mmol) followed by anhydrous DMA (2 ml) and the vessel was flushed with nitrogen whilst stirring vigorously and heating to 65° C. TMS-Cl (9 μl, 0.07 mmol) and 1,2-dibromoethane (6 μl, 0.07 mmol) were added and the reaction was stirred at 65° C. for 30 mins, followed by the dropwise addition of N-Boc-3-iodoazetidine (133 mg, 0.47 mmol) as a solution in anhydrous DMA (1 ml). The reaction was then cooled to room temperature and methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (100 mg, 0.28 mmol) was added as a solution in anhydrous DMA (2 ml). The resulting solution was degassed with nitrogen for 5 mins after which Pd(dppf)Cl2.DCM (7 mg, 0.01 mmol) and copper (I) iodide (3 mg, 0.02 mmol) were added as solids. The reaction was heated to 80° C. for 16 h and then cooled to room temperature followed by the addition of saturated NH4Cl solution (50 ml). The aqueous phase was extracted with EtOAc (3×100 ml), and then the combined organic phases were washed with brine (2×50 ml), dried with Na2SO4, filtered and evaporated. The residue was purified over a 5 g Isolute column using 10-30% EtOAc in heptane as the eluent to afford the title compound as a colourless oil (77 mg, 62%). LC-MS 98%, 2.19 min (3.5 minute LC-MS method), m/z=433.2, 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=1.6 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.31 (t, J=8.7 Hz, 2H), 3.94 (dd, J=14.4, 5.5 Hz, 4H), 3.89 (s, 3H), 3.77-3.64 (m, 1H), 3.31 (td, J=11.4, 2.7 Hz, 2H), 3.06 (q, J=7.0 Hz, 2H), 2.99-2.87 (m, 1H), 2.46 (s, 3H), 1.65 (ddd, J=11.1, 8.6, 6.0 Hz, 4H), 1.46 (s, 9H), 0.85 (dd, J=13.1, 6.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=2[OH:17])=[C:5]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:4]=1.Cl[CH2:30][C:31](Cl)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]([C:10]2[C:11]3[O:17][CH2:30][C:31](=[O:32])[NH:16][C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:18])=[C:5]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(C(=O)NCc2ccc(C(F)(F)F)cc2N2CCCCC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2C(=O)NCc2ccc(C(F)(F)F)cc2N2CCCCC2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-amino-2-hydroxybenzamide 24b (830 mg, 2.1 mmol) was dissolved in 10 ml of DMF and at 0° C. TEA (0.58 ml, 2 equiv.) and chloroacetyl chloride (0.2 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 2 hours. K2CO3 (580 mg, 2 equiv.) was added and the reaction was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 1 as eluant gave 460 mg of a white solid. Yield=50% 1HNMR (DMSO, 200 MHz) δ 1.57 (2H, bs), 1.69 (4H, bs), 2.84 (4H, m), 4.58 (2H, d, J=5.2 Hz), 4.69 (2H, s), 7.03 (2H, m), 7.30 (2H, m), 7.45 (2H, m), 8.70 (1H, bt), 10.85 (1H, bs); [M+1] 434.1 (C22H22F3N3O3 requires 433.4).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([OH:10])CO)=[CH:5][N:4]=[C:3]1[N+:11]([O-:13])=[O:12].CO>O>[CH3:1][N:2]1[C:6]([CH:7]=[O:10])=[CH:5][N:4]=[C:3]1[N+:11]([O-:13])=[O:12]
Reactant: Cn1c(C(O)CO)cnc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: Cn1c(C=O)cnc1[N+](=O)[O-]

Procedure:
To a solution of 3.15 g. of 1-methyl-2-nitro-5-(1,2-dihydroxyethyl)imidazole in 200 ml. of methanol, a solution of 3.6 g. of NaIO4 in 85 ml. of water is added with stirring. The precipitate which forms is filtered off and washed with methanol which is then added to the filtrate. By evaporation to dryness under vacuum a residue is obtained which is extracted several times with ethyl acetate. After concentration of the collected extracts, a crystalline product is obtained, which after recrystallization from ethyl acetate melts at 114°-115° C. Yield 2.5 g. (96%).
Reaction SMILES: [C:1]([CH:9]([CH2:13]OC)[CH2:10][O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.O>[C:1]([C:9]([CH2:10][O:11][CH3:12])=[CH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(COC)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C=C(COC)C(=O)c1ccccc1
Reaction time: 5 h
Yield: 73 %

Procedure:
An 84 g sample of 91% pure 2-benzoyl-1,3-dimethoxy propane 1 was heated with 4.2 g (5 wt %) of p-toluene sulfonic acid (p-TSA) to 80° with stirring. After 5 hr. a second 4.2 g sample of p-TSA was added. A third p-TSA addition of 2 g was made after another 5 hr. This mixture was left stirring for 6.5 hrs longer and then cooled. The reaction mixture was diluted with ml of Et2O and 100 ml H2O added. This mixture was then neutralized to pH=6-7 with dilute Na2CO3 and the organic layer dried over MgSO4. Filtration and removal of the ether in vacuo left an orange liquid, 2, which was distilled at 0.1 mm and 76° C. Yield: 73%. Purity: 93%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[NH2:39][NH2:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:39][NH2:40])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NN)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure E, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 82 mg, 0.176 mmol) in CH2Cl2 (8 ml) was added EDC (51 mg, 0.264 mmol) and DMAP (26 mg, 0.256 mmol), followed by hydrazine (7 mg, 0.264 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])(=O)[CH2:2][CH3:3]>C(OC(=O)C)(=O)C>[CH2:2]([C:1]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:3]
Reactant: CCC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1nc2ccccc2c(=O)o1
Yield: 93.6 %

Procedure:
A mixture of 2-Propionylamino-benzoic acid (1.0 g, 5 mmol) and acetic anhydride (10 mL) were heated to reflux for 3 hours until TLC indicated that no more starting material remained. The remaining acetic anhydride was removed in vacuo. Toluene (2 mL) was added and then removed in vacuo. This was repeated 2 more times to try and remove final traces of acetic anhydride. The product was obtained as a pale yellow solid (820 mg, 90%). 1H NMR (CDCl3) δ 1.37 (t, 3H, J=7.6 Hz), 2.73 (q, 2H, J=7.6 Hz), 7.50 (t, 1H, J=7.6 Hz), 7.57 (d, 1H, J=80 Hz), 7.79 (t, 1H, J=7.7 Hz), 8.19 (d, 1H, J=8.1 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:39]([O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C@H:54]([N:65]([CH3:67])[NH2:66])[C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C1C=CC=CN=1)C>ClCCl.C(OCC)(=O)C>[CH2:39]([O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C@H:54]([N:65]([CH3:67])[NH:66][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=[CH:49][CH:48]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(O)CCNC(=O)NCc1ccccc1
Reactant: CN(N)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 3-(3-benzylureido)propanoic acid (Compound VIII-1) 267 mg (1.20 mmol) in dichloromethane 5 ml, N-hydroxybenzotriazole 203 mg (1.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 288 mg (1.50 mmol) were added and the mixture was stirred at room temperature for 0.5 hr. (S)-benzyl 3-(4-(benzyloxy)phenyl)-2-(1-methylhydrazinyl)propanoate (Compound XVIII-1) 390 mg (1.00 mmol) and a solution of dimethylaminopyridine 61 mg (0.50 mmol) in dichloromethane 1 ml were added to the reaction mixture and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate solution 50 ml twice, water 50 ml twice and brine 50 ml and the organic phase was dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral elution by chloroform:methanol=100:0 to 95:5) to obtain the title compound 0.31 g (52.0%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.2 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester (intermediate 15) (1.7 g, 3.60 mmol), 10 ml of trifluoroacetic acid (130 mmol) in 10 ml of dichloromethane, and 1 ml of water, in a 100 ml round-bottomed flask equipped with a magnetic bar, is stirred for 2 hours at room temperature. The reaction medium is evaporated to dryness and the residue obtained is washed with ethyl ether to give 1.31 g of 4-fluoro-benzenesulfonic acid 2-aminobenzothiazol-6-yl ester in the form of the trifluoroacetic acid salt (white powder) in a yield of 83%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C@H:22]3[CH2:26][CH2:25][O:24][CH2:23]3)[N:15]=2)[N:3]=1.Cl.[OH-].[Na+]>CCO>[Cl:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C@H:22]3[CH2:26][CH2:25][O:24][CH2:23]3)[N:15]=2)[C:5]=1[NH2:9]
Reactant: Nc1nc(Cl)c(NC=O)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Yield: 87.4 %

Procedure:
A mixture of N-[2-amino-4-chloro-6-({6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-amino)pyrimidin-5-yl]formamide (10.00 g, 26.40 mmol) and hydrochloric acid (6 M, 22 mL) in EtOH (100 mL) was heated at reflux for 15 h, cooled, basified with aqueous sodium hydroxide (5-M, 50 mL) and concentrated in vacuo to remove the EtOH. The resulting mixture was extracted with dichloromethane (×2) and the combined organic extracts were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (8.09 g, 87%) as a pink solid; LC-MS retention time 1.52 min; (M+H)+ 351.
Reaction SMILES: [C:1]1([C:10]([OH:12])=O)[CH:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:35]1([C@H:41]([NH2:44])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([C@H:41]([NH:44][C:10]([C:1]2[CH:2]=[CH:3][N:4]3[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:12])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccn2c1CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1ccn2c1CCCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid (Comp. No. 8b) (6.22 g, 37.7 mmol) in dimethylformamide (125 ml) was added 1-hydroxybenzotriazole (5.60 g, 41.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.94 g, 41.4 mmol). The mixture was stirred for 30 min at 25° C., then (R)-1-phenyl-propylamine (6.11 g, 45.2 mmol) was added and the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h. The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added and the mixture was extracted 3 times with ethyl acetate, the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid, then 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness. The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 9.33 g (88%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 5): Rt=3.15 min; m/z=283.15 (M+H+).
Reaction SMILES: C(OC1C=CC(C(NC[C@H](N2CCN(S(C)(=O)=O)CC2)C(O)=O)=O)=CC=1)CCC.[CH2:30]([O:37][C:38]1[CH:62]=[CH:61][C:41]([C:42]([NH:44][CH2:45][C@@H:46]([C:57](=[O:60])[NH:58][OH:59])[N:47]2[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]2)=[O:43])=[CH:40][CH:39]=1)[C:31]1C=CC=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:44][CH2:45][C@@H:46]([C:57](=[O:60])[NH:58][OH:59])[N:47]2[CH2:48][CH2:49][N:50]([S:53]([CH3:56])(=[O:54])=[O:55])[CH2:51][CH2:52]2)=[O:43])=[CH:61][CH:62]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CS(=O)(=O)N1CCN([C@@H](CNC(=O)c2ccc(OCc3ccccc3)cc2)C(=O)NO)CC1
Agent: CCCCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Product: CCCCOc1ccc(C(=O)NC[C@@H](C(=O)NO)N2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
In a manner similar to example 2-6, starting from 200 mg (0.5 mmol) of (S)-3-(4-butoxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid, 100 mg (55%) of 4-benzyloxy-N—[(S)-2-hydroxycarbamoyl-2-(4-methanesulphonylpiperazin-1-yl)ethyl]benzamide are obtained in the form of a beige solid having a melting point of 130° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:9].[CH3:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>CN(C)C=O>[CH3:23][S:24][CH2:25][CH2:26][C:27](=[O:28])[NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([OH:22])[CH2:11][O:10][CH2:8][CH3:9])=[CH:21][CH:20]=1
Reactant: CCOCC(O)COc1ccc(N)cc1
Reactant: CSCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCC(O)COc1ccc(NC(=O)CCSC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolved in 4 ml of dimethylformamide were 1.46 g of triethylamine and 1.52 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. A 1.10 g quantity of 3-methylmercaptopropionyl chloride was added to the solution with ice-cooling. The mixture was stirred at room temperature for 12 hours and the reaction mixture was concentrated. The residue was extracted with chloroform and the chloroform layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water and concentrated. Ether was added to the residue and the crystals formed were filtered off to give 1.52 g of 2-{4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyl methyl sulfide in 67.4%, M.P. 79° to 81° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH:11]=[C:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[C:28]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O.CN(C=O)C>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:13]([C:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH:11]=2)=[O:15])=[CH:37][CH:38]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)C1=CCN(c2ncccn2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)C2=CCN(c3ncccn3)CC2)cc1
Reaction time: 1.5 h
Yield: 534.8 %

Procedure:
To a suspension of 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (60.4 mg, 0.194 mmol) and DMF (cat) in CH2Cl2 (1 mL) was added (COCl)2 (0.027 mL, 0.31 mmol). The mixture was stirred for 90 minutes, diluted with PhMe (0.5 mL), concentrated under reduced pressure to dryness, and dissolved in CH2Cl2 (1.5 mL). To the solution were added pyridine (0.027 mL, 0.33 mmol), DMAP (cat), and 4-tert-butylaniline (0.037 mL, 0.023 mmol). The mixture was stirred 1 hour, diluted with water and extracted with CH2Cl2, dried (Na2SO4), and purified by flash chromatography (7% EtOAc/CH2Cl2) to provide 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (4-tert-butyl-phenyl)-amide as a white solid (54.2 mg, 0.123 mmol, 63%): MS (ESI+) m/z 337 (M+H)+, m/z 334 (M−H)−; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.31 (s, 9 H), 2.59 (m, 2 H), 4.04 (t, J=5.6 Hz, 2 H), 4.44 (q, J=3.1 Hz, 2 H), 6.54 (t, J=4.7 Hz, 1 H), 6.75 (m, 1 H), 7.36 (m, 3 H), 7.47 (m, 2 H), 8.35 (d, J=4.7 Hz, 2 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:6]2[C:11](=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[NH:13][C:14]=1[CH3:15])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>ClCCl>[C:1]([C:4]1[CH:5]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:6]2[C:11]([O:12][CH2:33][CH3:34])=[N:10][CH:9]=[N:8][C:7]=2[NH:13][C:14]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2nc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1ncnc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
140 mg (0.38 mmol) of 6-acetyl-7-methyl-5-(2-methyl-4-oxo-4H-chromen-8-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one are suspended under an argon atmosphere in dichloromethane (7 ml), 219 mg (1.15 mmol) of triethyloxonium tetrafluoroborate are added, and the mixture is stirred at RT for 12 h. The reaction mixture is then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 9 mg (6% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:33][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Reactant: COc1ccc(CN2CCNCC2)cc1
Product: COc1ccc(CN2CCN(C(=O)Oc3ccc(NC(=O)CC4CCCCC4)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-(4-methoxybenzyl)-piperazine, preparative HPLC (Method C) (49%, white crystals). HPLC-MS m/z=466.3 (M+1), Rt: 2.85 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]#[N:16])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O[CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[NH2:21][C@@H:19]([CH3:20])[CH2:18][N:13]1[CH:12]=[C:11]([C:15]#[N:16])[C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=2)=[N:14]1
Reactant: N#Cc1ccc(-c2[nH]ncc2C#N)cc1Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1cc(C#N)c(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile (0.9 g, 3.94 mmol) dissolved in dry THF (15 ml), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.690 g, 3.94 mmol) and triphenyl phosphine (1.549 g, 5.90 mmol) dissolved in dry THF (15 ml) were loaded into a flask and cooled to 0° C. with an ice bath. Di-tert-butyl azodicarboxylate (1.360 g, 5.90 mmol) was added slowly and stirred for 10 min while keeping the temperature at 0° C. The temperature was allowed to rise to RT and the mixture was stirred overnight. Next day the mixture was evaporated and the intermediate deprotected by adding 10% HCl/EtOH solution (40 ml) and stirring overnight at RT. The mixture was again evaporated and the residue extracted with DCM/water. The pH of aqueous phase was adjusted to 12 by adding 2 M NaOH and extracted again with DCM. The organic phase was isolated with phase separator and evaporated. The product was used in the next step without further purification. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 4.27-4.39 (m, 3H), 6.50 (s, 2H), 8.02 (dd, 1H), 8.15-8.19 (m, 2H), 8.79 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:27])[N:21]=2)[C:9]2[C:10]([C:16]([OH:18])=O)=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:18])[N:19]2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:27])[N:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(Nc2ccc(=O)n(C)n2)c2ccc(Cl)cc2)c(C(=O)O)nn1C
Solvent: CO
Solvent: ClCCl
Product: Cc1c2c(nn1C)C(=O)N(c1ccc(=O)n(C)n1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1-methyl-6-oxo-1,6-dihydropyridazin-3-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid Step 32.3). tR: 3.94 min (HPLC 1); tR: 0.87 min (LC-MS 2); ESI-MS: 370 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 3.44 (s, 3H) 3.84 (s, 3H) 6.29 (s, 1H) 6.96 (d, J=9.8 Hz, 1H) 7.29-7.41 (m, 4H) 8.21 (d, J=9.8 Hz, 1H).