Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]2=[O:20])=[CH:7][CH:6]=1)=[O:3].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[CH3:18][C:14]1([CH3:19])[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)[C:12](=[O:20])[CH2:13]1
Reactant: CC1(C)CC(=O)N(c2ccc(OC(=O)Cl)cc2)C(=O)C1
Reactant: C1CN(CC2CC2)CCN1
Product: CC1(C)CC(=O)N(c2ccc(OC(=O)N3CCN(CC4CC4)CC3)cc2)C(=O)C1

Procedure:
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (Method C) (45%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 1.83 min.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[F:13].[CH:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[CH2:15].Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([CH:14]=[CH2:15])[CH2:17][CH2:18]2)=[C:4]([F:13])[C:5]=1[F:12])[CH3:11]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: C=CC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC1CCC(O)(c2ccc(OCC)c(F)c2F)CC1
Temperature: 53 °C
Reaction time: 0.5 h
Yield: 135.6 %

Procedure:
Seventh Step: 1.76 g of well dried magnesium and 10 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 53° C. 17.2 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 56° C., followed by stirring for 30 minutes. Thereafter, 6.0 g of the compound (16) dissolved in 10 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was then separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 18.5 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-vinylcyclohexanol (17) as a yellow liquid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.O.O.[NH2:14]N>CCO>[C:1]1([OH:11])[N:14]=[N:2][C:3]([OH:10])=[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=12
Reactant: O=C1NC(=O)c2cnccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1nnc(O)c2cnccc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To 2H-pyrrolo[3,4-c]pyridine-1,3-dione 1 (25.01 g, 169 mmol) dissolved in EtOH (250 mL) and H2O (250 mL) was added hydrazine hydrate (23 ml, 464 mmol). The solution was warmed to reflux and stirred for 1 h. After cooling to 40° C., the solution was brought to pH 4 with 5 N HCl whereupon precipitation of a light yellow solid occurred. After cooling to room temperature, the precipitate was filtered, washed with water, air dried for 2 h, and dried under high vacuum for 24 h at 40° C. to provide a quantitative yield of pyrido[3,4-d]pyridazine-1,4-diol 2. 1H NMR (d6-DMSO) δ 11.67 (bs, 2H), 9.33 (s, 1H), 9.02 (d, J=5.5 Hz, 1H), 7.89 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34]>O1CCCC1.C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:40][CH3:41])[CH2:33][CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCN(CC)CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2 hours with nitrogen bubbling through it. A solution of 3-diethylaminopropylamine (6.8 g, 0.0522 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was evaporated under reduced pressure to give a white solid. The solid was triturated with water (50 ml), filtered and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice with water to yield a white solid. The solid was dissolved in hot isopropyl alcohol and filtered. Addition of water and cooling to room temperature gave a white solid which was collected by filtration and rinsed with water to give 4.33 g (61%) of a solid. A 1.0-g sample of the solid was dried at high vacuum, mp 172° -174° C.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[CH:16][C:12]3[NH:13][N:14]=[N:15][C:11]=3[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].I[CH3:23]>CN(C)C=O>[CH3:23][N:15]1[C:11]2[CH:10]=[C:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[OH:8])[CH:17]=[CH:16][C:12]=2[N:13]=[N:14]1
Reactant: OC(c1ccccc1)c1ccc2[nH]nnc2c1
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc2ccc(C(O)c3ccccc3)cc21
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A mixture of 22.5 parts of α-phenyl-1H-benzotriazole-5-methanol, 4.8 parts of a sodium hydride dispersion 50% and 90 parts of N,N-dimethylformamide was stirred till hydrogen production had ceased. After the addition of 14.2 parts of iodomethane, stirring was continued for 30 minutes at room temperature. The mixture was concentrated. The concentrate was taken up in 50 parts of water and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by filtration over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The two isomers were separated by crystallization from ethyl acetate. The first isomer was further purified by crystallisation from ethyl acetate. The product was filtered off and dried, yielding 3 parts (12.5%) of 1-methyl-α-phenyl-1H-benzotriazole-6-methanol; mp. 145° C. (int. 71).
Reaction SMILES: C(Cl)Cl.[C:4]([OH:15])(=O)[C:5]1[CH:13]=[CH:12][C:8](C(O)=O)=[CH:7][CH:6]=1.C([N:18](CC)CC)C.[Cl-].[CH3:24][OH:25]>CN(C=O)C>[O:25]1[C:24]2[CH:13]=[CH:12][CH:8]=[CH:7][C:6]=2[CH2:5][C:4](=[O:15])[NH:18]1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CO
Reactant: CCN(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1Cc2ccccc2ON1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Into 50 mL methylene chloride was dissolved 0.682 g (2 mmol) of the above intermediate terephthalic acid, followed by 5 drops DMF and 3.88 mL (48 mmol) triethylamine The mixture was cooled in an ice bath, and 0.42 mL (4.8 mmol) oxayl chloride was added in one portion. After 30 min 10 mL MeOH was added and ice bath was removed. After stirring an additional 30 min, the mixture was shaken between EtOAc (100 mL) and cold dilute HCl (100 mL). The organic layer was washed with satd NaHCO3 (100 mL), dried (MgSO4), and evaporated. Crystalline desired benzoxazinone (456 g, 66%) was obtained from a concentrated methylene chloride-hexane solution.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4]([CH2:17][OH:18])=[CH:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][C:4]1[C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:6][CH2:7][C@H:2]([CH3:1])[CH:3]=1)(=[O:29])=[O:28]
Reactant: CCCCCCCCC[C@@H]1OC[C@H](C)C=C1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC[C@@H]1OC[C@H](C)C=C1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2S,5R)-(5,6-dihydro-5-methyl-2-nonyl-2H-pyran-3-yl)methanol (10 mg) and triethylamine (17 ml) in dry dichloro-methane (0.5 ml) was added methanesulfonyl chloride (10 ml) at 0° C. The mixture was allowed to warm to room temperature, and stirred for 30 min. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography gave (2S,5R)-(5,6-dihydro-5-methyl-2-nonyl-2H-pyran-3-yl)methyl methanesulfonate (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH:23]=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C=O)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution (2.6 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (100 mg) in THF were added a solution (1.0 M, 0.534 mL) of trimethyl(trifluoromethyl)silane (190 mg) and tetrabutylammonium fluoride in THF under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 M hydrochloric acid (0.5 ml), and the mixture was further stirred for 3 hr. Distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (91.7 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:45][O:44][C:42]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a 100 mL round bottom flask were added the TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.8164 g, 1.64 mmol, 1.0 equiv), DMAP (0.542 g), CH2Cl2 (40 mL) and triethylamine (6 mL). The mixture was cooled in an ice bath and a solution of methyl chloroformate (0.550 g, 5.82 mmol, 3.5 equiv) in CH2Cl2 (10 mL) was added. The reaction mixture was allowed to slowly warm to rt and stirred overnight. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 1.5 min, flow rate 25 mL/min) to give 0.5020 g (69%) of (R)-tert-butyl 3-((S)-4-(methoxycarbonyl-amino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate. LC-MS (3 min) tR=1.91 min, m/z 463 (MNa+), 441 (MH+), 343 341; 1H NMR (400 MHz, CDCl3) □ 7.37-7.36 (m, 1H), 7.28-7.17 (m, 3H), 4.90 (br s, 2H), 4.37 (d, J=12.0 Hz, 1H), 3.97 (d, J=12.3 Hz, 1H), 3.64 (s, 3H), 3.16-3.04 (m, 2H), 2.58-2.49 (m, 2H), 1.98-1.86 (m, 2H), 1.76-1.70 (m, 1H), 1.61-1.56 (m, 1H), 1.45 (s, 9H), 1.48-1.13 (m, 5H); 13C NMR (100 MHz, CDCl3) □ 157.60, 155.31, 146.51, 134.31, 129.36, 126.72, 125.96, 123.76, 80.08, 77.65, 52.21, 46.45, 44.91, 44.56, 40.91, 35.97, 28.42, 25.33, 25.25, 24.34.
Reaction SMILES: Br.[F:2][C:3]1[C:4]([CH3:14])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([OH:13])[CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23][O:24][CH3:25].O>CN1C(=O)CCC1.C1(C)C=CC=CC=1>[F:2][C:3]1[C:4]([CH3:14])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH2:22][CH2:23][O:24][CH3:25])[CH:7]=2
Reactant: COCCBr
Reactant: Cc1nc2cc(O)ccc2cc1F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COCCOc1ccc2cc(F)c(C)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a suspension of 3-fluoro-2-methylquinolin-7-ol hydrobromide (0.37 g, 1.43 mmol) and Cs2CO3 (1.08 g, 3.31 mmol) in NMP (6 mL) was added 1-bromo-2-methoxyethane (0.230 g, 1.66 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. Water (10 mL) and toluene (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (2:1 hexane/ethyl acetate) to give 3-fluoro-7-(2-methoxyethoxy)-2-methylquinoline (0.234 g, 0.995 mmol, 90.1% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:27])[C@@H:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:34][C:29]([CH2:28][C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][N:8]([C:11](=[O:27])[C@@H:12]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:7][CH2:6]2)=[CH:30][CH:31]=1
Reactant: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)[C@H](Cc2cccs2)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid methyl ester (5.63 mmol; 3.17 g) in THF (30 mL) and methanol (20 mL) was added a 1M solution of sodium hydroxide (16.9 mmol; 16.9 mL) and the resulting mixture was heated to reflux for 48 hours. The resulting mixture was then evaporated and a 1N hydrochloric acid solution (200 mL) was added to the residue. A white precipitate formed that was separated via filtration to yield 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid. MS (ESI) m/z 547.44 [M+H]+.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6]1[C:7]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)[N:11]=1.O>CO>[O:23]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]3[N:11]=[C:6]([N:5]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:4][CH2:3][OH:2])[C:7]4[CH2:27][NH:26][CH2:25][CH2:24][C:8]=4[N:9]=3)=[CH:14][CH:15]=2)=[CH:20][N:21]=[CH:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Hydrochloric acid (2 M, 2 ml) was added to a solution of tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (150 mg, 0.28 mmol, Example 1a) in methanol (4 mL). Water (2 mL) was added and the solution was stirred at 70° C. for 30 min. The residual solvent was evaporated under reduced pressure and the crude product dissolved in DMSO. Purification by preparative HPLC afforded 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (72 mg, 54.8%). MS (ESI+)/(ESI−) m/z 429/427
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:6])[C:4]#[CH:5].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>Cl>[CH2:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]#[CH:5]
Reactant: C#CCO
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: C#CCOCc1ccccc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Alternatively, solid potassium hydroxide (12.3 g, 0.22 mole) was stirred with propargyl alcohol (6.0 ml, 0.11 mole) and benzyl chloride (12.8 ml, 0.11 mole) at 60° C. for 16 hours. After cooling to 25° C., hydrochloric acid (80 ml, 3.0M aqueous solution) was added and extracted with hexanes (100 ml, 50 ml). The combined organic extracts were dried over magnesium sulfate and the solvent evaporated. The residue was distilled at 100 torr to afford propargylbenzyl ether as a colorless liquid (bp 140° C., 11.2 g, 71% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]1([CH3:24])[C:16]([C:21](Cl)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[CH3:24][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 65.5 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), o-toluoyl chloride (0.69 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (30 mL) provided 2-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 209-210° C.;Anal. Calcd. for C20H19NO2: C, 78.66; H, 6.27; N, 4.59; Found: C, 78.52; H, 6.28; N, 4.67.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2(O)[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[NH:12][C:11]2=[O:22])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].OC1C2C(=CC=CC=2)[NH:27]C1=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.S(Cl)(Cl)(=O)=O>>[NH2:27][C:10]1([C:9]2[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[CH:7][CH:8]=2)[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]([S:43]([C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[C:11]1=[O:22]
Reactant: O=C1Nc2ccccc2C1O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Solvent: O=S(=O)(Cl)Cl
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2)c2cc(F)c(C#N)cc21

Procedure:
The title compound was prepared using 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile as 3-hydroxy-1,3-dihydroindol-2-one IV and 4-methoxyphenylsulfonyl chloride as sulfonyl chloride VII in analogy to example 1.1 to 1.3.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)[CH3:2].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].C(NC)C>CN(C=O)C>[CH2:1]([N:3]([CH3:4])[C:9](=[O:10])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CCNC
Solvent: CN(C)C=O
Product: CCN(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
Triethylamine (12.84 g, 127.11 mmol) and p-nitrophenyl chloroformate (63.56 mmol, 12.8 g) were added to a room temperature solution of N-ethylmethylamine (2.50 g, 42.37 mmol) in dry DMF (70 mL) under an argon atmosphere. After 2 h, the reaction mixture was quenched with water, diluted with EtOAc (200 mL), washed with water (2×100 mL), and brine (75 mL). All volatiles were removed under reduced pressure and the residue was purified by SiO2 column chromatography using 10% EtOAc/hexanes to afford compound 4-nitrophenyl ethyl(methyl)carbamate (5.8 g, 76%) as a yellow oil. TLC: 20% EtOAc/hexanes, Rf≈0.50; 1H NMR (CDCl3, 300 MHz) δ 8.18-8.21 (m, 2H), 7.25-7.29 (m, 2H), 3.37-3.46 (m, 2H), 3.05 and 2.97 (s, 3H for two rotamers in 60/40 ratio), 1.17-1.22 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH2:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH:23][C:28]([NH:27][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCN=C=O
Reactant: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCN)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)NCCCc1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine (0.0324 mmol) [Example 35] in tetrahydrofuran (2 mL) was treated with n-propyl-isocyanate (0.0324 mmol). The solution was stirred at room temperature for 12 hours and then treated with water (3 mL). The resulting precipitate was filtered, then washed with water and then dried under vacuum at 50° C. to give the title compound as a beige solid. MS: 394 (MH+). HPLC (Method C): RT=3.25 minutes.
Reaction SMILES: C(O)(C(F)(F)F)=O.O1CCCCC1[O:14][NH:15][C:16]([C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:27][CH:26]([NH:28][S:29]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)(=[O:31])=[O:30])[CH2:25]2)=[N:22][CH:23]=1)=[O:17]>C(Cl)Cl.CO>[OH:14][NH:15][C:16]([C:18]1[CH:23]=[N:22][C:21]([N:24]2[CH2:27][CH:26]([NH:28][S:29]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)(=[O:31])=[O:30])[CH2:25]2)=[N:20][CH:19]=1)=[O:17]
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(NO)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
TFA (0.60 ml) was added to a solution of N-(tetrahydro-2H-pyran-2-yloxy) 2-{3-[(2-napthylsulfonyl)amino]azetidin-1-yl}pyrimidine-5-carboxamide (156 mg, 0.32 mmol) in DCM (10 ml) and MeOH (10 ml) at r.t. and the solution stirred at r.t. for 24 h. Further TFA (0.40 ml) was added and stirring continued for a further 18 h. The reaction mixture was concentrated in vacuo and the TFA was removed by azeotroping with DCM to yield a white foam. Trituration in hot DCM (15 ml) and MeOH (1 ml) gave a white precipitate which upon cooling to r.t. was isolated by filtration affording the title compound as a white solid (82 mg, 50%). LCMS purity 100%, m/z 400 [M+H]+, 1H NMR (400 MHz, d5-DMSO) δ: 3.64 (2H, m), 4.12 (2H, t), 4.31 (1H, br s), 7.71-7.76 (2H, m), 7.84 (1H, d), 8.09 (1H, d), 8.18-8.22 (2H, m), 8.49 (1H, s), 8.57 (3H, s), 9.01 (1H, s), 11.07 (1H, s).