Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].N1CCCCC1>CCO>[NH2:10][CH2:9][C:11]1[C:12](=[O:13])[NH:14][C:3]([CH3:4])=[C:2]([F:1])[C:6]=1[CH3:7]
Reactant: CC(=O)C(F)C(C)=O
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(CN)c(C)c1F
Temperature: 85 °C

Procedure:
A mixture of 3-fluoro-2,4-pentanedione (247 mg, 2.10 mmol), cyanoacetamide (176 mg, 2.1 mmol, 1 equiv) and piperidine (0.21 mL, 2.1 mmol, 1 equiv) in 3 mL of EtOH was heated at 85° C. for 16 h, resulting in a clear but dark brown solution. The mixture was concentrated in vacuo. The residue was taken up in 2 mL of 1N HCl to give a suspension, which was filtered. The tan solids collected were dried under vacuum to give the desired product as 80 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[C:13]([C:20](O)=[O:21])=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=2)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:12]3[C:13](=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=3)[C:20]2=[O:21])[CH:3]=1
Reactant: CC(C)n1cc(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)n1
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1cc2c(n1)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Step 42.2). tR: 4.25 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 417 [m+H]+(LC-MS 2); Rf=0.51 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.46 (m, 6H) 3.43 (s, 3H) 4.54-4.67 (m, 1H) 6.16 (s, 1H) 7.20-7.27 (m, 2H) 7.32-7.38 (m, 2H) 7.87 (s, 1H) 7.88-7.90 (m, 1H) 7.91-7.93 (m, 1H).
Reaction SMILES: [C:1](=O)([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)[O:2]C1C=CC=CC=1.[NH2:22][NH2:23]>CO>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:2])[NH:22][NH2:23]
Reactant: CN1C(C)(C)CC(OC(=O)Oc2ccccc2)CC1(C)C
Reactant: NN
Solvent: CO
Product: CN1C(C)(C)CC(OC(=O)NN)CC1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 250 ml 3-neck flask was added 20.0 grams (0.069 mole) of phenyl 1,2,2,6,6-pentamethyl-4-piperidinyl carbonate and 100 mls of methanol. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 3.8 grams (0.076 mole) of 64% aqueous hydrazine. The hydrazine was added slowly to the stirring methanol solution at room temperature. There was a slight exotherm. The reaction mixture was stirred for 5 hours at room temperature at which point liquid chromatography indicated the reaction was complete. The methanol was stripped off on a rotating evaporator under reduced pressure and the residue was dissolved in 150 ml MtBE. The MtBE solution was washed 3 times with 25 ml portions of 5% NaOH saturated with sodium chloride to remove the phenol that was generated. The MtBE layer was dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue was a white solid (m.p. 90°-94° C.) weighing 14.3 grams (90.5% crude yield). Liquid chromatography indicated the product was one component. The infrared spectrum contained a strong carbonyl peak at 1710 cm-1 and a moderate peak at 1625 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][NH:17][CH2:18][C:12]3=[C:11]([C:21]([NH:23][C@@H:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:35]([O-])(=O)C.[K+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][N:17]([CH3:35])[CH2:18][C:12]3=[C:11]([C:21]([NH:23][C@@H:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccc(F)c(F)c2)n2c1CNCC(C)(C)C2)C(C)(C)C
Reactant: CC(=O)[O-]
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccc(F)c(F)c2)n2c1CN(C)CC(C)(C)C2)C(C)(C)C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
The product from step 2 above (181 mg, 0.23 mmol) was dissolved in 2 mL of THF and treated sequentially with 37% aqueous formaldehyde (63 μL, 2.30 mmol) and potassium acetate (45 mg, 0.46 mmol) and the mixture stirred for 10 minutes. Sodium triacetoxyborohydride (146 mg, 0.69 mmol) was added and stirring continued for 1.5 hours. The reaction was quenced by the addition of 5 mL of saturated aqueous NaHCO3 and 10 mL of DCM was added. The layers were separated and the aqueous layer was extracted with 10 mL of DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO RediSep-4, gradient elution 0%-20% EtOH:acetonitrile). The residue was lyophilized from aqueous acetonitrile to give 85 mg (9% yield) of (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6,6,8-trimethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide as a white powder. LCMS (+ESI) m/z: 462.3 [MH]+1. 1H-NMR (DMSO d6) δ 8.07 (m, 1H), 7.64-7.48 (m, 3H), 7.35-7.28 (m, 1H), 5.06-4.32 (bs, 2H), 4.24 (d, 1H), 3.91-3.66 (m, 2H), 2.52 (d, 3H), 2.40-2.32 (m, 2H), 2.27 (s, 3H), 1.08 (s, 9H), 0.85 (s, 9H), 0.66 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[O:20][C:21]1[CH:22]=[CH:23][N:24]=[C:25]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:26]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 56.2 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.329 g, 2.88 mmol), ethyl 4-chloro-3-(2-chloropyridin-4-yloxy)benzoate (0.900 g, 2.88 mmol), potassium phosphate (0.673 g, 3.17 mmol), Pd2(dba)3 (0.132 g, 0.144 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.083 g, 0.144 mmol) were reacted to provide ethyl 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate (0.631 g, 56% yield). 1H NMR (d6-DMSO) δ 10.99 (s, 1H), 8.20 (d, 1H), 7.92 (d, 1H), 7.83-7.87 (m, 2H), 6.51-6.57 (m, 3H), 4.32 (quartet, 2H), 2.20 (s, 3H), 1.31 (t, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[NH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]=23)[CH2:21][CH2:22]1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Reactant: NCC1CCNCC1
Product: Fc1ccc(-c2cc(NCC3CCNCC3)c3sccc3n2)cc1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (60 mg, 0.23 mmole) in 4-aminomethylpiperidine (1 mL) is heated at 160° C. oil bath under N2 for 4 hours. The reaction mixture is cooled to room temperature and purified on preperative tlc plate to give N-(4-piperidinylmethyl)-5-(4-fluorophenyl) thieno[3,2-b]pyridin-7-amine (15 mg, 19% yield) as a colorless oil. This material is dissolved in 1 mL ethyl acetate. Ethyl acetate saturated with HCl (2 mL) is added and then concentrated to afford N-(4-piperidinylmethyl)-5-(4-fluorophenyl) thieno[3,2-b]pyridin-7-amine dihydrochloride (compound 1) as a greasy oil. The salt is triturated with ether, collected by filtration, washed with ether and dried in vacuo, m.p. >260° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(OCC)(=O)C>O1CCCC1.O>[O:14]=[C:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
4.9 g of 1-(4-aminophenyl)-4-piperidinone were suspended in a mixture of 30 ml of tetrahydrofuran and 9 ml of water under argon and treated with 3.3 g of sodium hydrogen carbonate. Then, a solution of 2.7 ml of ethyl chloroformate in 20 ml of tetrahydrofuran was added dropwise at room temperature while stirring vigorously and, after completion of-the addition, the mixture was stirred for a further 1 h. After adding water and ethyl acetate the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and concentrated. The residue (6.6 g) was chromatographed over silica gel 60 with ethyl acetate/hexane mixtures (1:2-1:0). Crystallization from diethyl ether yielded 3.8 g of ethyl 4-(4-oxo-piperidin-1-yl)-phenylcarbamate as grey crystals. M.p.: 145°-146°.
Reaction SMILES: [S:1]([O:21][CH2:22][CH3:23])([O:3][CH2:4][C:5]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])=[O:2].[OH2:24]>CC#N.C(Cl)Cl>[S:1]([O:21][CH2:22][CH3:23])([O:3][CH2:4][C:5]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])(=[O:24])=[O:2]
Reactant: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCOC(C)(COS(=O)(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of sulfite 6 (24.5 g, 69.5 mmol) in MeCN (200 mL), CH2Cl2 (200 mL) and water (300 mL) is added NaIO4 (29.7 g, 139.0 mmol) and RuCl3 (10 mg, 0.05 mmol). The mixture is stirred at 23° C. for 5 hours. The mixture is filtered through Celite and extracted with CH2Cl2 (2×200 mL). The combined organic layers are washed with saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfate 7 (23.3 g, 91%) as a colorless oil: Rf (15% EtOAc/hexane)=0.41; IR (thin film, cm−1) 2931, 2860, 1737, 1467, 1403, 1380, 1196, 1179, 1012, 925, 858; 1H NMR (600 MHz, CDCl3) δ 4.34 (q, J=7.2 Hz, 2H), 4.09 (s, 2H), 3.43 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.38 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.51 (m, 4H), 1.40 (t, J=7.2 Hz, 3H), 1.37 (s, 3H), 1.34-1.24 (m, 12H), 0.86 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 98.2, 72.4, 69.7, 60.9, 31.6, 29.8, 25.9, 22.6, 20.8, 14.5, 14.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31]Cl)=[CH:25][CH:24]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[O:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:46]4[CH2:47][CH2:48][N:43]([C:41]([CH:37]5[CH2:38][CH2:39][CH2:40][O:36]5)=[O:42])[CH2:44][CH2:45]4)=[CH:25][CH:24]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(-c2cnc(Cc3ccc(OCCCl)cc3)nc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCc1ccc(-c2cnc(Cc3ccc(OCCN4CCN(C(=O)C5CCCO5)CC4)cc3)nc2)cc1
Temperature: 90 °C
Yield: 51 %

Procedure:
{4-[2-(4-{{2-[4-(Tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino]-acetic acid tert-butyl ester can be synthesized by the following procedure. To a solution of (4-{2-[4-(2-chloro-ethoxy)-benzyl]-pyrimidin-5-yl}-benzylamino)-acetic acid tert-butyl ester (0.032 mmol) (from Example 5y) in anhydrous DMF is added sodium iodide (0.0384 mmol) and 1-(tetrahydro-2-furoyl)-piperazine (0.16 mmol). The reaction mixture is heated at 90° C. for 8 h. Purification by preparative LCMS (ACN gradient 10-90%) affords {4-[2-(4-{2-[4-(tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino}-acetic acid tert-butyl ester (51%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 4.3 (m, 4H), 3.85 (m, 4H), 3.76 (m, 3H), 3.52 (m, 4H), 2.35 (m, 4H), 2.0 (m, 4H), 1.48 (s, 9H). MS (m/z) (M+1)+ 617.2.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:21][C:22]6[O:26][C:25]([C:27]([OH:29])=O)=[C:24]([C:30](=[O:33])[NH:31][CH3:32])[C:23]=6[CH:34]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C1C=CC2N(O)N=[N:47][C:45]=2C=1.CCN=C=NCCCN(C)C.Cl.CN.CCN(CC)CC>CN(C=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([NH:47][CH3:45])=[O:29])=[C:24]([C:30]([NH:31][CH3:32])=[O:33])[C:23]=6[CH:34]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc2c1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of compound 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (50 mg, 0.09 mmol), HOBT (24 mg, 0.17 mmol), EDCI (102 mg, 0.53 mmol), methanamine hydrochloride (42 mg, 0.62 mmol) and Et3N (72 mg, 0.71 mmol) in DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue was purified by prep-TLC (DCM:MeOH=200:1) to give the product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (20 mg, yield: 39%). 1H NMR (CDCl3, 400 MHz) δ 10.49 (br s, 1H), 8.81 (s, 1H), 7.68 (s, 1H), 7.49 (s, 2H), 7.24˜7.17 (m, 3H), 7.12 (d, J=8.2 Hz, 1H), 6.88˜6.81 (m, 1H), 6.01 (s, 2H), 3.39 (s, 3H), 3.12 (d, J=5.2 Hz, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 578.
Reaction SMILES: [CH:1]1([CH2:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CBr)CCCCCCCCCCC1.[OH:29][CH2:30][CH2:31][NH2:32]>>[OH:29][CH2:30][CH2:31][NH:32][CH2:13][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: NCCO
Reactant: OCC1CCCCCCCCCCC1
Agent: BrCC1CCCCCCCCCCC1
Product: OCCNCC1CCCCCCCCCCC1

Procedure:
Methyl cyclododecanecarboxylate was reduced according to Method B2b, Step 1 to give cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to Method B2b, Step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N-(2-hydroxyethyl)-N-(cyclododecylmethyl)amine. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(cyclododecylmethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclododecylmethyl)-1,3 -thiazolidine.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:24][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:24][O:18][C:14]1[CH2:13][CH:12]([C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:17][CH2:16][N:15]=1
Reactant: C[O+](C)C
Reactant: O=C1CC(c2nc(-c3ccccc3)no2)CCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCC(c2nc(-c3ccccc3)no2)C1
Temperature: 0 °C
Yield: 90.8 %

Procedure:
Add 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-2-one (1.0 g, 4.11 mmol) to a solution of trimethyloxonium tetrafluoroborate (1.06 g, 6.99 mmol) in dichloromethane (8.2 mL) at 0° C. Stir the reaction overnight at room temperature and pour into an ice cold solution of saturated aqueous sodium bicarbonate. Separate and extract the aqueous layer with additional dichloromethane. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound as a crystalline white solid (0.96 g). 1H NMR (CDCl3) δ 1.9 (m, 1H), 2.17 (m, 1H), 2.65-2.72 (m, 2H), 3.43 (m, 1H), 3.58 (m, 1H), 3.7 (s, 3H), 3.75 (m, 1H), 7.43-7.53 (m, 3H), 8.0-8.1 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:24][CH2:25][CH2:26][CH3:27])=[C:7](/[C:18](/[CH3:23])=[C:19](/[F:22])\[CH2:20][OH:21])[CH:8]=2)[O:3]1.C[N+]1([O-])CCOCC1>>[CH3:1][C:2]1([CH3:28])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:24][CH2:25][CH2:26][CH3:27])=[C:7](/[C:18](/[CH3:23])=[C:19](/[F:22])\[CH:20]=[O:21])[CH:8]=2)[O:3]1
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(c1ccccc1)=CC(C)(C)O2
Agent: C[N+]1([O-])CCOCC1
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure M, (2E)-3-(2,2-dimethyl-4-phenyl-7-propoxy-2H-chromen-6-yl)-2-fluoro-but-2-en-1-ol (Compound 89, 145 mg, 0.38 mmol) and 4-methylmorpholine N-oxide (90 mg, 0.76 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([CH2:29][S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[NH2:33][S:30]([CH2:29][C:28]1[CH:34]=[CH:35][C:25]([CH2:24][NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:22])=[CH:26][CH:27]=1)(=[O:31])=[O:32]
Reactant: NCc1ccc(CS(N)(=O)=O)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(CS(N)(=O)=O)cc4)cc3)c2)o1

Procedure:
N-[4-(Aminosulphonylmethyl)benzyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(aminomethyl)benzylsulphonamide using method H. NMR; δH [2H6]—DMSO 9.17,(1H, t), 8.00,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.56-7.51,(3H, m), 7.33,(4H, m), 6.82,(2H, b), 4.50,(2H, d), 4.23,(2H, s), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 2.90 min, MH+ 477.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(OC([N:22]1[CH2:25][C@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]1[C:32](O)=[O:33])=O)(C)(C)C>>[C:26]1([C@H:24]2[CH2:25][NH:22][CH:23]2[C:32]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)c1ccc(N)c2cccnc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C1C(=O)O
Product: NC(=O)c1ccc(NC(=O)C2NC[C@@H]2c2ccccc2)c2cccnc12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 27 by using 5-aminoquinoline-8-carboxamide coupled with (3S)-1-(tert-butoxycarbonyl)-3-phenylazetidine-2-carboxylic acid, followed by de-Boc to afford Example 30. LC-MS (M+H=347, obsd=347).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:10][CH2:9][C@@H:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:11])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc([C@@H](O)CO)cn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (R)-1-(6-methylpyridin-3-yl)ethane-1,2-diol (13.72 g, 0.085 mol), 1H-imidazole (13.55 g, 0.197 mol), and CH2Cl2 (180 mL) at 0° C. was added tert-butyldimethylsilyl chloride (15.31 g, 0.098 mol). The reaction mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred overnight. The mixture was washed with water (300 mL) and extracted with CH2Cl2. The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (0-50% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10]OCC1C=CC=CC=1)=O)(C)(C)C.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH2:10][C@@H:9]([NH:8][CH3:6])[CH2:19][OH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CNC
Product: CN[C@@H](CO)CN(C)C

Procedure:
By using N-(t-butoxycarbonyl)-O-benzyl-(L)-serine (2.50 g) and 50% aqueous dimethylamine (3 ml) as starting materials, the title compound (0.58 g) was obtained in the same manners as those of Reference Example 34, (1), Reference Example 107, (2) and Reference Example 7, (2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([F:20])[C:16](F)([F:18])[F:17])=[CH:11][C:10]=2[O:21][CH3:22])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:20])=[C:16]([F:17])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[N:3]=1
Reactant: COc1cc(C(F)C(F)(F)F)ccc1Oc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)=C(F)F)ccc1Oc1cccc(F)n1
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of 2-fluoro-6-[2-methoxy-4-(1,2,2,2-tetrafluoroethyl)phenoxy]pyridine (0.078 mmol; 25 mg) under argon in THF (1 mL) at 0° C. was added dropwise a one molar solution of LiHMDS in THF (0.094 mmol; 94 μl). The reaction mixture was let come back to rt for 16 h. Concentration and purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70) afforded the title compound (10 mg; 0.033 mmol; 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[O:20])[CH:13]=1.[ClH:21]>ClCCl.C(O)C>[ClH:21].[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:19]([NH:18][C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)=[O:20])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: O=C=Nc1cccnc1
Reactant: Cn1ccc2c(N)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cn1ccc2c(NC(=O)Nc3cccnc3)cccc21
Reaction time: 17 h

Procedure:
A solution of the aminoindole (D10) (0.44 g; 3.01 mM) in dichloromethane (10 ml) was added dropwise to a solution of 3-pyridyl isocyanate (D4) (prepared from 3-pyridine carbonyl azide (0.51 g; 3.4 mM) in toluene) at room temperature. The reaction mixture was stirred for 17 h, then cooled and the precipitate filtered off to give the crude product (1 g; 100%). This was dissolved in hot ethanol and ethereal hydrogen chloride added to afford the title compound as its hydrochloride salt (0.74 g; 81%), m.p 238° C.