Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8](Br)=[CH:9][N:10]=1)=[O:5])[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>CCN(CC)CC.C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncc(Br)n1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc(C#C[Si](C)(C)C)n1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
To a solution of 800 mg (3.43 mmol) of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester in Et3N (10 mL) and THF (10 mL) was added 33 mg (0.17 mmol) of CuI and 120 mg (0.10 mmol) of Pd(PPh3)4. Trimethylsilylacetylene (0.48 mL, 3.4 mmol) was then added and the reaction was heated at 70° C. under N2. After 12 h, the mixture was cooled and filtered though a pad of celite, and then concentrated and chromatographed (0-50% EtOAc in hexanes) to give 1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethyl ester as a brown oil (205 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH2:19]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([NH:19][CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 61 %

Procedure:
0.42 g (0.00112 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 1.4 ml of 8M methylamine in ethanol were stirred at room temperature in a mixture of 11 ml of ethanol and 11 ml of dioxane for 48 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. The product-containing fractions were suspended in 25 ml of diethyl ether, treated in an ultrasound bath and diluted with 45 ml of hexane. The suspension was suction filtered and the filter material was dried in a high vacuum. There was obtained 0.224 g (61%) of (4-benzenesulphonyl-6-bromopyridin-2-yl)-methylamine as white crystals; m.p.: 145-148° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:44])[CH2:9][O:10][C:11]([C:13]2[CH:14]=[C:15]([CH:41]=[CH:42][CH:43]=2)[CH2:16][N:17]2[C:21](=[O:22])[C:20]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:19]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:18]2)=[O:12])[CH2:4][CH2:3]1.Cl>O1CCOCC1>[O:22]=[C:21]1[C:20]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:18][N:17]1[CH2:16][C:15]1[CH:14]=[C:13]([CH:43]=[CH:42][CH:41]=1)[C:11]([O:10][CH2:9][C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:44])=[O:12]
Reactant: CN1CCN(C(=O)COC(=O)c2cccc(CN3CN(c4ccccc4)C4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(C(=O)COC(=O)c2cccc(CN3CN(c4ccccc4)C4(CCNCC4)C3=O)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.16 g, 0.26 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-(4-methylpiperazin-1-yl)-2-oxoethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([CH3:11])([CH2:6][CH2:7]1)[C:4](=[O:12])[CH2:3]2.Cl[C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=1[N+:22]([O-:24])=[O:23].CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([NH:1][C:2]23[C:8]([CH3:9])([CH3:10])[C:5]([CH3:11])([CH2:6][CH2:7]2)[C:4](=[O:12])[CH2:3]3)[C:19]([Cl:20])=[CH:18][N:17]=1
Reactant: CC12CCC(N)(CC1=O)C2(C)C
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC12CCC(Nc3c(Cl)cnc(N)c3[N+](=O)[O-])(CC1=O)C2(C)C
Temperature: 60 °C
Yield: 100 %

Procedure:
4-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (8) (1.1 g, 5.29 mmol)) and 4,5-dichloro-3-nitropyridin-2-amine (1 g, 4.81 mmol) were taken in IPA (30 ml) and DIPEA (4.6 ml, 26.44 mmol)) was added to the reaction mixture which was then heated at 60° C. for 24 h when TLC confirmed completion of reaction. The reaction mixture was cooled to rt and concentrated in vacuuo. Pure product (9) (1.63 g, 92%) was obtained as a yellow solid after purification by column chromatography using silica gel (100-200 mesh). NMR: δ (1H, 400 MHz, CDCl3): 0.87 (3H, s), 0.97 (3H, s), 1.05 (3H, s), 1.44-1.54 (1H, m), 1.70-1.80 (1H, m), 1.90-2.20 (1H, m), 2.30-2.40 (1H, m), 2.47 (1H, dd, J=3.2, 18.0 Hz), 2.88 (1H, d, J=18.4 Hz), 6.55 (2H, s), 7.85 (1H, s), 7.96 (1H, s) LCMS: (254 nm): [M+H]+ 339.10 (86.27%)
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrCCCBr
Reactant: COC(=O)C=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/c1ccccc1OCCCBr
Yield: 89.4 %

Procedure:
To a solution of methyl 2-hydroxycinnamate (1.31 g; 7.33 mmol) in 50 ml acetone was added 1,3-dibromopropane (1.50 ml; 14.8 mmol) and K2CO3 (4.36 g; 13.4 mmol). The mixture was heated to reflux for 12 h, cooled to r.t, diluted with hexane (50 ml), filtered and finally concentrated to afford the title product (1.96 g; 50% pure), which was used as such in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)[CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:33]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:30][C:27]([CH3:28])([CH3:29])[C:26](=[O:31])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:33][C:9]=3[CH:10]=2)[CH2:14][CH3:15])[CH3:17])=[CH:19][C:20]=1[CH3:32]
Reactant: CCC(c1cc2cc(C(=O)OC)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(c1cc2cc(C(=O)O)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-ethylpropyl}-benzofuran-5-carboxylic acid methyl ester (5.30 g, 11.8 μmmol) in methanol (30.0 mL) and THF (30.0 mL) is treated with NaOH (2.0 M, 60 mL). The resulting mixture is stirred at RT for 16 h. The mixture is concentrated and neutralized with HCl (5 N) till pH˜3, and extracted with EtOAc (2×100 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (4.85 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([NH:19][C:20]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=3)=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[C:5]#[N:6].[CH2:28]([CH2:30][NH2:31])[OH:29]>CN1C(=O)CCC1>[Cl:27][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([NH:19][C:20]3[CH:25]=[C:24]([NH:31][CH2:30][CH2:28][OH:29])[N:23]=[CH:22][N:21]=3)=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[C:5]#[N:6]
Reactant: NCCO
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Nc4cc(Cl)ncn4)c3s2)c(Cl)c1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Nc4cc(NCCO)ncn4)c3s2)c(Cl)c1
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
A mixture of 3,5-dichloro-4-[4-(6-chloropyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile (0.030 g, 0.07 mmol) and ethanolamine (12.6 μL, 0.21 mmol) in NMP (0.7 mL) was subjected to microwave irradiation at 150° C. for 75 minutes. Further ethanolamine (5.0 μL, 0.08 mmol) was added and the mixture subjected to microwave irradiation at 160° C. for 45 minutes then 190° C. for 45 minutes. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were combined and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the desired compound as an off-white solid (0.014 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 8.40-8.34 (m, 3H), 8.16 (s, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.22 (br s, 1H), 6.85 (br s, 1H), 4.72 (t, J=5.4 Hz, 1H), 3.52 (q, J=5.9 Hz, 3H). LCMS (Method C): RT=3.10 min, m/z: 458 [M+H+].
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(C(F)(F)F)=O.OS(O)(=O)=O>[Br:8][C:18]1[CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:14][C:13]=1[C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 24 h

Procedure:
NBS (125.0 g, 697.5 mmol) was slowly added to a solution of TFA:H2SO4 (5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0 mmol) at RT. The solution was stirred for 24 h then poured over 5 kg of ice. The resulting suspension was filtered and washed with a 1:1 MeOH:H2O solution (200 mL) and dried in a vacuum oven. MS (ES+):258.1, 260.1 (M+H)+. Calc'd for C10H12BrNO2:257.01.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].N1C=CC=CC=1.[Cl:40][CH2:41][C:42](OC(=O)CCl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:40][CH2:41][C:42]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:7]([C:13]4[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(NN)c3cc2-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccn4c(CCl)nnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 16-2 (1.2 g, 2.7 mmol) in CH2Cl2 (10 ml) was added DMAP (0.03 g, 0.03 mmol) and pyridine (0.4 ml, 5.4 mmol) followed by chloroacetic anhydride (0.5 g, 3.0 mmol). The reaction mixture was stirred at room temperature for 2 h before adding additional chloroacetic anhydride (0.2 g, 0.9 mmol). After stirring for an additional 10 min the solvent was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc (3×30 ml). The combined organic layers were washed with water, brine and dried (Na2SO4/MgSO4). Removal of the solvent afforded the desired product 26-1 as a red powder. MS calculated: 500.2. Found 500.1
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) suspension of dry NaH (0.512 g, 21.4 mmol) in anhydrous DMF (10 mL) under an Argon atmosphere, a solution of 4-bromophenol (3.11 g, 17.8 mmol) in anhydrous DMF (20 mL) was added dropwise over 2-3 min. The mixture was stirred at 0° C. for 10 min and then allowed to warm to rt over 30 min. To the resulting white suspension was added 1-bromo-2-(2-methoxyethoxy)ethane (2.66 mL, 19.6 mmol) dropwise over 2 min and the mixture was stirred at rt for 30 min and then at 65° C. for 1.5 h. After cooling to rt, the mixture was concentrated under reduced pressure to an oily suspension, diluted with brine (80 mL), and the mixture was extracted with EtOAc (3×60 mL). The combined extracts were washed with brine (2×25 mL), dried over Na2SO4, filtered, and concentrated to give compound 85a as a mobile, pale amber-colored oil, used in the following reaction without further purification. Mass spectrum (LCMS, ESI pos.): Calcd. for C11H15BrO3, 275.0/277.0 (M+H). found 275.2/277.1
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=S)[NH:5][C:4]1=[S:15])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CC(C)=O>[CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:4]1=[S:15])[CH3:2]
Reactant: C1COCCN1
Reactant: CCc1nc2c([nH]1)c(=S)[nH]c(=S)n2CC
Solvent: CC(C)=O
Product: CCc1nc2c([nH]1)c(N1CCOCC1)nc(=S)n2CC
Temperature: 25 °C

Procedure:
The product of stage (i) (14.42 g) was refluxed in 78.4 ml (900 mmoles) of morpholine for 30 hours. After cooling to room temperature the reaction product was suspended in 100 ml of acetone and the title product (16.49 g) collected and washed.
Reaction SMILES: [CH2:1]([O:3][C:4]1([CH3:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:6]=2[O:5]1)[CH3:2].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][N:16]([CH3:20])[C:17](=[O:18])[O:13][C:12]1[C:6]2[O:5][C:4]([O:3][CH2:1][CH3:2])([CH3:14])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCOC1(C)Oc2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC1(C)Oc2cccc(OC(=O)N(C)C)c2O1
Yield: 77 %

Procedure:
2-Ethoxy-2-methyl-4-hydroxy-1,3-benzodioxole, prepared as in Example 1, (10g) was dissolved in dry acetone (100 ml). Dimethylcarbamoylchloride (8g) and potassium carbonate (12g) were added and the mixture stirred and heated under reflux for six hours. The mixture was then filtered and the solvent evaporated from the filtrate under reduced pressure. Distillation of the residue gave 2-ethoxy-2-methyl-1,3-benzodioxol-4-yl dimethylcarbamate (9.5g, 77% yield), boiling oint 120°-124° C/0.3 mmHg.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C(O)C.O1CCCC1>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OC)nc3)oc2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoic acid (168 mg), ethyl 3-(methylamino)propanoate (63 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg), hydroxybenzotriazole monohydrate (74 mg) and triethylamine (67 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL). 1N Lithium hydroxide (0.6 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (118 mg, 60%).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22].C(O)(=O)C.C([BH3-])#N>CO>[CH3:23][C:20]([NH:19][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:18])([CH3:17])[CH3:1])[CH:4]=2)[N:14]=1)([CH3:24])[CH2:21][OH:22]
Reactant: CC(C)(N)CO
Reactant: C[Si](C)(C)c1cccc(-c2cccc(C=O)n2)c1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(CO)NCc1cccc(-c2cccc([Si](C)(C)C)c2)n1
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of Example 226A (1.00 g, 3.92 mmol) in methanol (20 mL) at ambient temperature was added 2-amino-2-methyl-1-propanol (0.349 g, 3.92 mmol), acetic acid (0.90 mL, 15.7 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.5 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1N NaOH. The organic layer was extracted with 1N aquoues HCl (×2) and the organic phase discarded. The aqueous layer was neutralized with 1N NaOH and extracted with EtOAc. The EtOAc extract was dried and concentrated to provide 700 mg (54%) of the title compound. MS (DCI+) m/z 329 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.97-7.90 (m, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.64-7.54 (m, 2H), 7.48 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 3.95 (s, 2H), 3.42 (s, 2H), 1.18 (s, 6H), 0.39-0.25 (m, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][NH:20][NH2:21])=[CH:17][CH:16]=1>>[NH2:10][C:6]1[NH:21][N:20]([CH2:19][C:18]2[CH:22]=[CH:23][C:15]([O:14][C:13]([F:24])([F:25])[F:12])=[CH:16][CH:17]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(OC(F)(F)F)cc1
Product: Nc1cc(=O)n(Cc2ccc(OC(F)(F)F)cc2)[nH]1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 20.6 g of 4-trifluoromethoxybenzylhydrazine, analogously to the procedure described in Example 1. 8.7 g of the compound identified above as colorless crystals of melting point 99°, corresponding to 32% of theory, are obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:32][CH:33]([C:39]([O-:41])=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH2:55][NH2:56]>O1CCOCC1>[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:32][CH:33]([C:39](=[O:41])[NH:56][CH2:55][C:54]1[CH:57]=[CH:58][CH:59]=[C:52]([O:51][CH3:50])[CH:53]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(CN)c1
Reactant: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)NCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.03 g of dicyclohexylcarbodiimide was added to 30 ml of a solution of 1.83 g of ethyl N-(N-benzyloxyleucyl)aminomalonate, 0.58 g of N-hydroxysuccinimide and 1.3 ml of (3-methoxybenzyl)amine in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove-the insoluble materials. The filtrate was diluted with 100 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. 1.49 g of the resulting yellow oily substance was purified by silica gel column chromatography (eluant: ethyl acetate/n-hexane=1/2)to obtain 0.96 g of ethyl N-(N-benzyloxyleucyl)-α-[N-(3-methoxybenzyl)carbamoyl]glycinate as a colorless oily substance.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]([C:27](=[O:30])[CH2:28]Cl)[CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:28][C:27]4=[O:30])=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)C)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Isopropylamine (2 mL, 48.72 mmol) was added to a solution of Example 57k (0.3 g, 0.59 mmol) in DMF (5 mL) and stirred at 80° C. for 3 h. The reaction mixture was concentrated, treated with water, and extracted with chloroform. The organic layer was washed with water, brine and concentrated to obtain the title compound which was purified using flash chromatography (silica gel, 2% methanol/chloroform). Yield: 0.16 g, (55.17%); 1H NMR (CDCl3): δ 1.10 (d, 6H, 2CH3), 2.7 (s, 3H, CH3), 2.8 (q, 1H, CH), 2.86 (t, 2H, CH2), 3.41 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 4.71 (s, 2H, CH2), 7.38 (d, 1H, Ar), 7.46 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][OH:19]>>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:16][C@@H:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][OH:19])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1-c1ccccc1
Yield: 64 %

Procedure:
2 g (10 mmol) of 2-phenylbenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3a, affording 2.1 g (64%) of the product.
Reaction SMILES: Br[C:2]1[C:3]([NH2:19])=[N:4][C:5]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:7]=1.[CH3:20][O-:21].[Na+]>CO>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:5]1[N:4]=[C:3]([NH2:19])[C:2]([O:21][CH3:20])=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: C[O-]
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Temperature: 70 °C
Yield: 46 %

Procedure:
3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62, 160 mg, 0.5 mmol) was suspended in methanol (5 mL), sodium methoxide was added (0.12 mL, solution 30% in methanol, 0.5 mmol) and the solution was heated to 70° C. for 2 hours. The mixture was cooled, the solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane. The organic layer was dried and concentrated. The residue was triturated with diethyl ether to provide the target compound as a brownish solid (62 mg, 46%)