Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.[ClH:19].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH2:25][CH2:24]1>>[ClH:19].[ClH:19].[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH3:18])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:28][CH2:27]2)[CH2:36][CH2:35]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: CC(C)CCOc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)CCOc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3-methyl-butyloxy)-1H-indole-2-carboxylic acid (84) (preparation see below) and amine 21.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([F:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([C:8]([F:15])=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(F)ccc(N)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
To a solution of methyl 2,6-difluoro-3-nitrobenzoate (25 g, 115 mmol) in MeOH (150 mL) was added 5% palladium on carbon (2.5 g). The mixture was stirred under H2 atmosphere (50 psi/25° C.) for 12 h. The catalyst was filtered, and the filtrate was concentrated under the reduced pressure to dryness to give the product of Step C (20 g, 93.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.95-7.10 (m, 2H), 3.86 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:25]1[C:24]2[NH:23][C:22](=[O:30])[C:21]3[S:31][CH:32]=[CH:33][C:20]=3[C:19]=2[C:18]([C:16]2[CH:15]=[CH:14][C:3]([CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:2]([F:1])[CH:17]=2)=[C:27]([O:28][CH3:29])[CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 46.6 %

Procedure:
Following General Procedure H, tert-butyl 2-fluoro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (300 mg, 0.64 mmol) was reacted with NCS (94 mg, 0.71 mmol) to afford the desired product (150 mg, 46%) as a yellow solid. ESI MS m/z 503 [C25H21ClFN2O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[C:22]([O:24]C)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:26]>C(#N)C.O.C(#N)C.O>[OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:15](=[O:26])[C:16]2[C:21]([C:22](=[O:24])[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1cc(CCCCC#CCCCC#CCO)c(O)c2ccccc12
Solvent: CC#N
Solvent: O
Product: O=C1C=C(CCCCC#CCCCC#CCO)C(=O)c2ccccc21
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
2-(12-Hydroxydodeca-5,10-diynyl)-1-hydroxy-4-methoxynaphthalene (80 mg) is dissolved in 1 ml of acetonitrile and 0.75 ml of water. This mixture is cooled in an ice bath and the addition of ceric ammonium nitrate (0.377 g) in 2 ml of 50% acetonitrile/water is carried out over 10 minutes. Stirring is continued an additional 30 minutes (after only 5 minutes a yellow precipitate forms). The above contents are poured into a separatory funnel and additional water is added. The mixture is extracted three times with methylene chloride and the combined organic extracts are washed with water, saturated sodium bicarbonate, and brine, dried with magnesium sulfate, filtered, and concentrated to provide 74.9 mg of the title compound as a yellow solid, mp 88°-89.5° C. By TLC (in 2% acetone/methylene chloride) the material is fairly clean, with a small amount of impurities at lower Rf. Drying the sample under low vacuum (0.2 mm) overnight changes the melting point slightly, mp 89°-90.5° C.
Reaction SMILES: [OH:1][C:2]1[NH:3][NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[C:12](Cl)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[OH:1][C:2]1[NH:3][N:4]([C:12](=[O:21])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: OC1=Nc2ncccc2NN1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CC#N
Product: O=C(C=Cc1ccccc1)N1NC(O)=Nc2ncccc21
Yield: 64.2 %

Procedure:
7.5 g (0.05 moles) of 3-hydroxy-1,2-dihydro-pyrido[2,3-e]-as-triazine are reacted with 17 g (0.102 moles) of cinnamoyl chloride in 150 ml of acetonitrile as described in Example 6. 9.0 g (65%) of the title compound are obtained; m.p.: 221°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([O:20]C(C)(C)C)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([OH:20])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
8-chloro-11-[(6S,8S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenzo[b,f]-1,4-oxazepine (0.211 g, 0.495 mmol), prepared as described above, was dissolved in trifluoroacetic acid (10 mL) and stirred for 15 minutes. The solvent was removed and the resulting residue was redissolved in methylene chloride (20 mL). Triethylamine (0.100 g, 0.991 mmol) was then added via syringe and the resulting solution was stirred for 1 hour. Washing with water (50 mL), drying over MgSO4 and concentrating resulted in a white solid (0.180 g, 99%); mp 94°-96° C.; Rf(35% acetone/hexanes): 0:15; HRMS (FAB) MH+ of C20H20N3 O2Cl, calculated 370.1322, found 370.1318.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[C:10]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)(=[O:12])[CH3:11]>C1COCC1>[Br:7][CH2:11][C:10]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)=[O:12]
Reactant: CC(=O)c1cc2ccccc2o1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
Pyridinium bromide perbromide (20 g) was added to a THF solution (200 ml) of 2-acetylbenzofuran (8.35 g). The reaction mixture was stirred at room temperature for 20 minutes. The precipitated crystals were collected by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the entitled compound (6.5 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:44][CH2:45][O:46][CH3:47]>CC#N>[CH3:47][O:46][CH2:45][CH2:44][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: COCCBr
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A mixture of estrone (10 g; 37 mmol), Nal (1.1 g, 7.4 mmol), Cs2CO3 (18.08 g; 55.5 mmol) and Br(CH2)2OCH3 (15 mL; 156 mmol) in CH3CN (200 mL) was refluxed for 1 h. The mixture was filtered over silica gel and washed successively with CH2Cl2 and EtOAc to give the ether (12.1 g; 99.4%); 1H NMR (300 MHz, CDCl3) δ 7.23 (d, 1H, J=8.6 Hz), 6.75 (dd, 1H, J=2.6, 8.6 Hz), 6.72 (s, 1H), 4.1 (t, 2H, J=4.4 Hz), 3.74(t, 2H, J=3.7 Hz), 3.44 (s, 3H), 2.87 (dd, 2H, J=4.25, 8.5 Hz), 2.48 (dd, 1H, J=8.4, 18.7 Hz), 0.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:19][NH2:20]>>[CH2:13]([C:12]1[C:6]2[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8](=[O:9])[NH:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)c1ccc(OC)cc1C(=O)O
Reactant: NN
Solvent: O
Product: CCCCc1n[nH]c(=O)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-pentanoylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[Se:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:30]([N:32]([CH2:35][CH2:36][NH:37][NH2:38])[CH2:33][CH3:34])[CH3:31].Cl>CN(C)C=O.CC(O)C>[ClH:1].[CH2:30]([N:32]([CH2:33][CH3:34])[CH2:35][CH2:36][N:37]1[C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]3[Se:7][C:8]4[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:38]1)[CH3:31]
Reactant: O=c1c2ccc(O)cc2[se]c2c([N+](=O)[O-])ccc(Cl)c12
Reactant: CCN(CC)CCNN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)[Se]c1cc(O)ccc1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 1.59 g (0.004 mole) of 1-chloro-6-hydroxy-4-nitro-9H-selenoxanthen-9-one in 12 ml of N,N-dimethylformamide with 0.85 ml of diisopropylethyl amine is added 0.85 ml of 2-(diethylaminoethyl)hydrazine. The cooling bath is removed and the mixture is stirred at 25° C. for 2.5 hours. Concentration of the reaction in vacuo leaves an orange solid. Trituration of the solid with boiling 2-propanol gives an orange powder which is dried in vacuo at 80° C. to afford 1.66 g of the dry product as a salt with 1.0 equivalents of hydrogen chloride; mp 255°-257° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].Cl.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:22]3[C:21](=[C:20]([F:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: 3-(2-Oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]1([C:12]2[O:16][N:15]=[C:14]([CH:17]3[CH2:22][CH:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:20][N:19]([C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])[CH2:18]3)[N:13]=2)[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C:9]1([C:12]2[O:16][N:15]=[C:14]([CH:17]3[CH2:22][CH:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=4)[CH2:20][N:19]([C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])[CH2:18]3)[N:13]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(c2nc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)no2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2nc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)no2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.6 ml (2.3 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 130 mg (0.230 mmol) of the compound from Example 85A in 0.25 ml of dioxane. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, again taken up in 0.25 ml of dioxane, and once more 0.6 ml (2.3 mmol) of a 4N solution of hydrogen chloride in dioxane was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated to dryness under reduced pressure and dried until the weight remained constant. Yield: 115 mg (92% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:15]=1[CH2:16][NH:17][CH2:18][CH2:19][CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[F:13][C:14]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:15]=1[CH2:16][N:17]([CH2:18][CH2:19][CH3:20])[C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCNCc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (245 mg, 1.474 mmol) in DMF (5 ml) was cooled in an ice-bath. N-(2,4-Difluorobenzyl)-N-propylamine (300.4 mg, 1.622 mmol) was added and then TBTU (521 mg, 1.622 mmol) followed by DIPEA (400 mg, 3.096 mmol). The mixture was stirred at room temperature overnight. Sodium hydrogencarbonate aqueous solution (sat.) was added. The mixture was extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using DCM/heptane (50:50), DCM and then MeOH/DCM (1:99, then 2:98) as eluant gave 336 mg the desired product, yield 68%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:55]=[O:56].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 9h (1.53 g, 2.1 mmol) was dissolved in 15 mL 1,4-dioxane, followed by addition of 3.4 mL 37% formaldehyde solution and 6.3 mL 1 M sodium hydroxide. The reaction mixture was stirred for 16 hour at 70° C., and was partitioned after 50 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (50 mL×3) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 91 (2.0 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[S:19].O>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([N:9]([CH3:10])[C:18](=[S:19])[O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Reactant: CNc1cccc(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
1.38 g of 2-methoxy-6-methylaminopyridine and 1.38 g of anhydrous potassium carbonate were added to 20 ml of acetone, to which 2.23 g of 2-naphthyl chlorothioformate dissolved in 20 ml of acetone was added at room temperature under stirring. The stirring was continued for 30 minutes under the same conditions and then the mixture was heated to reflux for 2 hours. The reaction mixture was poured into water after it was cooled to room temperature and the products were extracted with benzene. The benzene solution was subsequently washed with water and aqueous saturated sodium chloride solution and then benzene was removed by distillation under reduced pressure after drying over anhydrous magnesium sulfate. The residue was purified by the column chromatography (eluted with benzene on a silica gel) to give 2.75 g of O-2-naphthyl N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate (Yield: 85%). A part of the product was recrystallized from acetone-hexane. Colorless crystalls having melting point of 95.5° to 97° C. were obtained.
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:89])[C@@H:83]([CH2:85][C:86]([OH:88])=[O:87])O>CC(C)=O>[CH3:35][CH:34]([CH3:36])[CH2:33][C@@H:32]([B:4]1[O:5][C@H:83]([CH2:85][C:86]([OH:88])=[O:87])[C:82](=[O:89])[O:3]1)[NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1)=[O:49])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.305 g, 0.278 mmol) and D-malic acid (130.3 mg, 0.33 mmol) were mixed in acetone (3 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 3 h. The slurry was filtered to collect solid 2-((R)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.410 g, 100%). [M+H] calculated for C23H28BN4O7, 483.2051. found, 483.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[CH3:2][O:3][C:4](=[O:13])[CH:5]([N:12]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(N)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(N=Cc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 8 (40.3 g, 0.2 mol) in dichloromethane (600 mL) was added triethyl amine (24.24 g, 0.24 mol) dropwise. After stirring for 30 min, benzaldehyde (21.2 g, 0.2 mol) was added dropwise, followed by the addition of MgSO4 (240 g, 2 mol). The mixture was stirred overnight. After filtration, the filtrate was evaporated to give compound 9 (49 g, 96.8%). 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 5.22 (s, 1 H), 7.30-7.39 (m, 6 H), 7.53-7.56 (m, 2 H), 7.82-7.85 (m, 2 H), 8.34 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.[N:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:35][C:29]1([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH2:30][CH2:31][N:32]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:33][CH2:34]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Reactant: OC1(c2ccncc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(c3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-4-yl)piperidin-4-ol (A4) (80 mg, 0.453 mmol) in methylene chloride (3 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol/hexane/ammonia solution (25% aq.) (100:10:10:1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:23])[C:13]1[C:20]([F:21])=[CH:19][C:16]([C:17]#[N:18])=[C:15]([Cl:22])[N:14]=1)(C(C)(C)C)(C)C>C(O)C.Cl.O>[Cl:22][C:15]1[N:14]=[C:13]([N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH3:23])[C:20]([F:21])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)c(C#N)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(CCCO)c1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
A mixture of 6-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(methyl)amino]-2-chloro-5-fluoronicotinonitrile (Example 310, 0.73 g, 2.04 mmol) in ethanol/HCl/water (95:1:4) (50 mL) was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was passed through a plug of silica gel with ethyl acetate as the eluent to give the product (0.5 g, 100%) as a waxy yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.54 (d, 1H), 3.65 (dt, 2H), 3.54 (t, 2H), 3.18 (d, 3H), 1.85-1.77 (m, 2H).