Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:23]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:2]1([NH:1][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:32][CH:33]=2)=[O:39])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)[CH3:22]
Reactant: CCOC(=O)CC1(N)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C(=O)OCc3ccccc3)C2)cc1
Yield: 30.6 %

Procedure:
To a solution of benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (260 mg, 0.85 mmol) and p-octylphenylisocyanate (215 mg, 0.93 mmol) in CH2Cl2 (3 mL) was added triethylamine (0.35 mL, 2.55 mmol) to give the title compound as a brown solid (140 mg, 31%). MS ESI 538.2 [M+H]+, calcd for [C31H43N3O5+H] 538.32.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>>[CH3:1][N:2]1[C:6]([NH:7][C:13](=[O:14])[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][C:4]([C:8]([F:9])([F:10])[F:11])=[N:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nc(C(F)(F)F)cc1N
Product: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Yield: 25.9 %

Procedure:
Using the procedure described in Example 161C, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (1.70 g, 10.3 mmol) and phenyl chloroformate (1.88 g, 12 mmol) were reacted to afford phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (0.760 g, 26%). LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[CH3:2].C1N=[CH:35][N:34](C(N2C=NC=C2)=O)[CH:33]=1.CNC.C(O)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:24]([C:23]1[C:17]2[O:16][C:15]([NH:14][CH:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)[CH2:13][CH2:12]3)=[N:19][C:18]=2[CH:20]=[CH:21][CH:22]=1)=[O:26]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)O)c4o3)CC2)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)N(C)C)c4o3)CC2)ccc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To the crude coupling product 2-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-benzo-oxazole-7-carboxylic acid (42.5 mg, 0.1 mmol, 1.0 equiv) dissolved in anhydrous DMF (1 mL) was added CDI (32.4 mg, 0.2 mmol, 2.0 equiv) and the reaction mixture stirred at 50° C. After 1 h, a solution of dimethylamine 5.6 M in ethanol (71 μL, 0.4 mmol, 4.0 equiv) was added and the reaction mixture stirred at 50° C. for another 24 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 9.0 mg (20%) of the title compound. MS (ESI): 452.0 [M+H]+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1cc(O)ccc1C=O
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde (Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0° C. was added tetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL of a 1M solution in THF). The pale-yellow solution was stirred for 30 minutes and quenched by the addition of ice cold H2O. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (20% EtOAc—hexanes) afforded 500.0 mg (96%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([O:23]C)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Oc2ccccn2)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Oc3ccccn3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-(pyridin-2-yloxy)biphenyl-3-carboxylate (460 mg, 1.4 mmol) in tetrahydrofuran (20 mL) was added 2.5 M aqueous lithium hydroxide solution (5.6 mL, 14 mmol). After being stirred at room temperature overnight, the mixture was acidified to pH=5 by addition of 2N aq. HCl and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (CD3OD, 300 MHz): 8.17 (d, 1H, J=3.2 Hz), 8.11 (s, 1H), 7.88 (td, 1H, J=8.0, 2.0 Hz), 7.65 (s, 1H), 7.58-7.52 (m, 3H), 7.29 (d, 2H, J=8.4 Hz), 7.16 (dd, 1H, J=7.2, 4.8 Hz), 7.06 (d, 1H, J=8.0 Hz), 2.38 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].O.[C:14](N)(C)(C)[CH3:15].FC(OB([O-])[O-])=C(F)F.[K+].[K+]>C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:9]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:2]=1[CH:14]=[CH2:15])[NH2:6]
Reactant: CC(C)(C)N
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: C=Cc1ccc(N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
4-Bromo-3-(trifluoromethyl)aniline (4.0 g, 16.7 mmol) was dissolved in isopropanol (20 mL), water (10 mL), and t-butylamine (5 mL). To the solution, potassium(trifluoro)vinylborate (4.0 g, 29.9 mmol), PdCl2(dppf)2.2-dichloromethane complex (300 mg, 0.37 mmol) were added. The resulting mixture was stirred under argon atmosphere at 80° C. for 20 hours and then concentrated. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting product was purified by silica-gel column chromatography (n-hexane:ethyl acetate=6:1) to give 3-trifluoromethyl-4-vinylaniline (2.475 g, 79%) as a light-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[F:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[N:48][CH:49]=1>>[NH2:24][C:19]1[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:4]2[CH:3]=[C:2]([C:46]3[CH:47]=[N:48][CH:49]=[C:44]([F:43])[CH:45]=3)[CH:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[N:18]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: OB(O)c1cncc(F)c1
Product: COc1ccc(Nc2ncc(-c3cncc(F)c3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoropyridin-3-ylboronic acid (Combi-Blocks Inc.), and was isolated as an orange crystalline solid (22%). m/z (ESI, +ve ion) 405.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.90 (1H, s); 9.09 (1H, d, J=2.7 Hz); 8.80 (1H, s); 8.75 (1H, d, J=2.7 Hz); 8.56 (2H, t, J=2.5 Hz); 8.19 (1H, dd, J=8.9, 2.8 Hz); 8.10 (1H, br. s.); 7.92 (1H, br. s.); 7.77 (1H, br. s.); 6.86 (1H, d, J=9.0 Hz); 3.86 (3H, s), 2.47 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:34][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(-c3ccno3)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 5-(4-bromomethyl-phenyl)-isoxazole analogous to Example 2c to afford 4-chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-N-(4-isoxazol-5-yl-benzyl)-benzenesulfonamide MS: m/e=488.1 (MH+).
Reaction SMILES: BrBr.[CH3:3][NH:4][C:5](=[S:16])[NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]>C(O)(=O)C>[CH3:3][NH:4][C:5]1[S:16][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]=1
Reactant: CNC(=S)Nc1cccc(C(=O)O)c1
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1nc2cccc(C(=O)O)c2s1
Temperature: 95 °C
Yield: 85.3 %

Procedure:
A solution of 163 g of bromine and 50 g of 100% acetic acid is added dropwise to a suspension of 212 g of 3-(N'-methylthioureido)-benzoic acid and 500 g of 100% acetic acid at 45-50° C. in the course of 2 hours. The mixture is then heated to 90-100° C. in the course of 2.5 hours and is allowed to react for a further 2 hours until the release of the gas has ended. After 150 g of acetic acid have been distilled off at 80-85° C. under reduced pressure, 200 g of water are added and the mixture is brought to pH 2 by dropwise addition of 30% sodium hydroxide solution. Filtration with suction at 70-80° C. and washing with water gives 179.2 g of the title compound of melting point: >330° C. HPLC analysis shows a content of 94.6% of the title compound, in addition to 3-4% of isomeric 2-methylamino-benzothiazole-5-carboxylic acid. Yield: 81.5% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.[Cl:16]([O-])=O.[Na+]>C(O)C>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[CH2:10]2
Reactant: [O-][Cl+][O-]
Reactant: CC(=O)Nc1cccc2c1CN(C)C2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(Cl)c2c1CN(C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(2,3-dihydro-2-methyl-1H-isoindol-4-yl)acetamide (20 g), hydrochloric acid (37%, 2.5 mL), and sodium chlorite (15%, 10 ml) in 96% ethanol (20 mL) was stirred at room temperature for 4 hours. The solvent was removed by evaporation, whereafter the residue was treated with saturated Na2CO3 in water to pH=7. The precipitated product was filtered off and washed with water and ether. Yield 1.1 g, mp 147-150° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].O=[C:5]1[CH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])=[CH:6]1.[OH-].[K+]>O.Cl.C(N)C>[CH2:1]([N:3]=[C:5]1[CH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])=[CH:6]1)[CH3:2]
Reactant: CCN
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCN=C1C=C(C)CC(C)(C)C1
Temperature: 10 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
Ethylamine (42 ml of a 70% solution in water, 530 mmol) is added slowly to a stirred mixture of isophorone (9.67 g, 70 mmol) and ethylamine hydrochloride (0.29 g, 3.5 mmol) at -7° C. After the addition is complete, the temperature of the mixture is allowed to rise to room temperature, and the mixture is stirred for a further 72 hours. The mixture is subsequently cooled to 10° C., and potassium hydroxide (44.9 g, 800 mmol) is added in portions. After 45 minutes, ice is added and the mixture is stirred. The organic phase is then separated, dried over sodium sulfate and evaporated in vacuo to give the crude product (11.0 g, 95%) as a yellow oil, which is used immediately without further purification in the following step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.Cl.[NH2:23][CH2:24][C@H:25]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:26]([O:28][CH3:29])=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:29][O:28][C:26](=[O:27])[C@@H:25]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:24][NH:23][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Acid 4-4 (100 mg, 0.36 mmol), amine 2-2 (105 mg, 0.36 mmol), EDC (88 mg., 0.46 mmol), HOBT (62 mg, 0.46 mmol) and NMM (137 μL, 1.2 mmol) were combined in 2 mL DMF. After 16 h the mixture was diluted with EtOAc, washed with water, sat. NaHCO3, 5% KHSO4, and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 65% EtOAc/hexane) provided 4-5 as an oil. Rf 0.32 (silica, 65% EtOAc/hexane).
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[N:17](C)[CH:13]2[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:1][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[NH:17][CH:13]2[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CN1C2CCC1C1CCC2N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN1C2CCC1C1CCC2N1

Procedure:
To a cold (0° C.) solution of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane (J. Med. Chem. 2000, 43, 2115-2123) and TEA in an DMF (1-2 ml) was added MeI. The mixture was allowed to warm to rt and stirred for 2-3 h. The rxn mixture was evaporated to dryness and partitioned between ether and satd. NaHCO3 and ether layer separated, washed with brine and dried (Na2SO4). Evaporation of ether afforded 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane as a light-brown oil. A stirred suspension of 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane in EtOH containing conc. HCl (0.5 ml) and 10% Pd—C was hydrogenated under balloon pressure of hydrogen overnight. The suspension was filtered and filtrate was added dry toluene (10-15 ml) and evaporated to dryness to afford the 9-methyl-9,10-diazatricyclo[4.2.1.12,5]decane and isolated as bis-HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14](O)=[O:15])[CH3:9])=[CH:4][CH:3]=1.[NH3:27].CO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([NH2:27])=[O:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: N
Solvent: CO
Product: C[C@H](Nc1cc(C(N)=O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To 500 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)_isonicotinatic acid (Example 141), was added 15 ml of 7N ammonia/methanol solution and the mixture was stirred at 100° C. for 3 days in a sealed tube. The solvent of the reaction solution was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 310 mg of the objective compound as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>CO.[Pt]=O>[CH2:12]([NH:16][CH:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]1)[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CCCCN
Agent: O=[Pt]
Solvent: CO
Product: CCCCNC1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h

Procedure:
2.0 g of platinum oxide were added to a solution of 155 g of 2,2,6,6-tetramethyl-4-piperidone and 80 g of butylamine in 300 ml of methanol. The resulting mixture was then hydrogenated under a hydrogen atmosphere in a Parr hydrogenation apparatus at room temperature for 5 hours. After completion of the reaction, the platinum catalyst was filtered off and the solvent was distilled from the filtrate under reduced pressure. The residue was purified by vacuum distillation, to give the desired product as an oil, boiling at 100°-101° C./5 mmHg (667 Pascals).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[CH:16]#[N:17]>>[OH:10][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:16]#[N:17]
Reactant: O=CCCc1ccccc1
Reactant: C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Product: N#CC(O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
In a 300 ml flask, 134 g of 3-phenylpropanal and 1.4 g of 10% aqueous sodium acetate solution were placed, to which 27 g of hydrocyanic acid was added in dropwise maintaining the reaction temperature at 20° to 25° C., thereafter the reaction mixture was kept standing for 30 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Si:7]([O:14][C@H:15]([CH2:26][CH3:27])[C:16]([O:18][Si](C(C)(C)C)(C)C)=O)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1>C(Cl)Cl.CN(C=O)C.O>[Si:7]([O:14][C@H:15]([CH2:26][CH3:27])[C:16]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1)=[O:18])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(N)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Oxalyl chloride (1.32 g, 10.43 mmol was added slowly to a stirred solution of tert-butyl(dimethyl)silyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}butanoate (Step 1) (2.77 g, 8.69 mmol) in DCM (10 mL) and DMF (three drops). After 1 h at ambient temperature, gas evolution had subsided and the reaction mixture was concentrated in vacuo to remove excess oxalyl chloride. The residue was dissolved in DCM (10 mL) and pyridine (0.89 g, 11.30 mmol) and 2-amino-5-picoline (1.03 g, 9.56 mmol) were added. The reaction mixture was kept at ambient temperature for 2 hrs. Water was added and the two phases were separated. The aqueous phase was extracted with DCM. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with heptane/EtOAc:5/2) to give the title compound as a colourless oil (2.0 g). 1H NMR (500 MHz, CDCl3) δ 8.91 (br s, 1H), 8.15 (d, 2H), 7.53 (m, 1H), 4.26 (t, 1H), 2.31 (s, 3H), 1.85 (m, 2H), 0.96 (m, 12H), 0.17 (m, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH2:28])=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:30][C:31]1[S:32][C:33]([CH2:36][C:37](O)=[O:38])=[CH:34][N:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH:28][C:37](=[O:38])[CH2:36][C:33]6[S:32][C:31]([CH3:30])=[N:35][CH:34]=6)=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(N)C=CN5C)CC1
Reactant: Cc1ncc(CC(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(NC(=O)Cc2cnc(C)s2)C=CN5C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.3 %

Procedure:
A mixture of Example 73d (0.02 g, 0.051 mmol), 2-(2-methylthiazol-5-yl)acetic acid (0.012 g, 0.077 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.029 g, 0.077 mmol) in N,N-dimethyl acetamide (0.5 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.153 mmol) and stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and washed with saturated aqueous sodium chloride. The aqueous layers were combined, saturated with solid sodium chloride and extracted with ethyl acetate (4×100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-15% methanol in dichloromethane). The material was further purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 10-100%) to provide 0.0258 g (78%) of the title compound as the TFA salt. 1H NMR (400 MHz, PYRIDINE-d5) δ 11.24 (s, 1H), 10.34 (s, 1H), 8.34 (d, J=2.44 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=2.75 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=8.54 Hz, 1H), 6.89 (s, 1H), 4.20 (s, 2H), 4.13 (s, 3H), 4.07 (s, 2H), 3.64 (m, 1H), 3.25 (m, 1H), 2.63 (m, 2H), 2.55 (s, 3H), 2.59 (m, 1H), 1.93 (s, 3H), 1.69 (m, 2H), 1.50 (m, 2H). MS (ESI+) m/z 531.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:4][CH:3]1[C:5]1[O:6][C:7]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:8]=2[C:9]=1[C:10]([NH:12][CH3:13])=[O:11].Cl[C:35]1[CH:36]=[CH:37][C:38]2[O:51][CH2:50][N:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[C:46]([F:49])[C:47]=4[CH:48]=[C:40]3[C:39]=2[N:52]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:2]1([F:1])[CH2:4][CH:3]1[C:5]1[O:6][C:7]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])[C:15]([C:35]3[CH:36]=[CH:37][C:38]4[O:51][CH2:50][N:41]5[C:42]6[CH:43]=[CH:44][CH:45]=[C:46]([F:49])[C:47]=6[CH:48]=[C:40]5[C:39]=4[N:52]=3)=[CH:14][C:8]=2[C:9]=1[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(C2CC2(F)F)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C2CC2(F)F)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
A mixture of 2-(2,2-difluorocyclopropyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (20 mg, 0.04 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (11 mg, 0.04 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), X-Phos (10 mg, 0.02 mmol) and K3PO4 (60 mg, 0.12 mmol) in DMF (2 mL) was stirred at 100° C. for 6 h. Water was added and the mixture was extracted with EtOAc. After concentration, the residue was purified by prep-TLC (PE:EA=1:3) to give the product of 2-(2,2-difluorocyclopropyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (2 mg, yield: 8%). 1H-NMR (MeOD, 400 MHz) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.60 (s, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.26˜7.20 (m, 2H), 6.93 (dd, J=8.0, 10.4 Hz, 1H), 6.11 (s, 2H), 3.64˜3.56 (m, 1H), 3.34 (s, 3H), 2.99 (s, 3H), 2.98 (s, 3H), 2.26˜2.17 (m, 2H). MS (M+H)+: 597.