Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCCO
Product: OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 4-pentyn-1-ol were converted to yield 5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as yellow oil, MS: 327 (M, 1 Cl).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7](Cl)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[OH:11][C@:12]([CH3:48])([CH2:46][OH:47])[C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:1]1[CH2:6][CH2:5][CH:4]([S:7]([O:47][CH2:46][C@:12]([OH:11])([CH3:48])[C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]2[S:41][C:40]([CH3:42])=[N:39][CH:38]=2)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CCOCC1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)C1CCOCC1

Procedure:
Prepared according to procedures described above, by reacting tetrahydro-2H-pyran-4-sulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C30H42N4O11S2 m/z: 699 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].CO[C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[C:11](OC)[C:12]=1OC.[Cl:21]C1C=C(C=CC=1)N.N#CN.[N+]([O-])(O)=O>O>[N+:1]([O-:4])([O-:3])=[O:2].[Cl:21][C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Agent: N#CN
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: NC(=[NH2+])Nc1cccc(Cl)c1

Procedure:
The 3-chlorophenylguanidinium nitrate starting material was prepared by the method described for 3,4,5-trimethoxyphenylguanidinium nitrate in Example 1 from 3-chloroaniline (10.35 g, 81.2 mmol), cyanamide (10.2 ml of a 50% w/v solution in water) and concentrated nitric acid (6 ml, 85.3 mmol) to give the desired product as a pale brown solid (12.5 g) m.p. 172-174°. δH (d6 DMSO) 9.75 (1H, br s), 7.52 (4H, br s), 7.45 (1H, t, J 7.8 Hz), 7.35-7.29 (2H, m) and 7.21 (1H, d, , 8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH3:21][S:22]CCl>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:22][CH3:21])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CSCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. 1-amino-2-nitro-4-thiocyanatobenzene is treated in 20 ml. dimethylformamide under nitrogen at 20°-25° C. with 1.14 g. sodium borohydride. After 1 hour 10 ml. of methylthiomethylchloride is added and the mixture stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column, then evaporated to dryness leaving 1-amino-2-nitro-4-methylthiomethylthiobenzene as a red solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:32][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(Nc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)c2cccnc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
190 mg of 4-[N-(3-pyridyl)amino]benzonitrile was dissolved in 5 ml of N,N-dimethylformamide, and 44 mg of 60% sodium hydride was added thereto under cooling with ice, followed by stirring at 40-50° C. for 30 minutes. Then, 273 mg of 4-benzyloxybenzyl chloride was added to the reaction mixture under cooling with ice, followed by stirring at room temperature for 2 hours. After the reaction mixture was poured into water, the product was extracted with chloroform. After the extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 234 mg of 4-[N-(4-benzyloxy-benzyl)-N-(3-pyridyl)amino]benzonitrile.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH:6][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCNC(=N)N)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.5 %

Procedure:
To a solution of 2.0 gm (8.9 mMol) arginine methyl ester hydrochloride and 1.5 gm (14.8 mMol) triethylamine in dimethylformamide (150 ml) was added 776 mg (7.4 mMol) acetic anhydride dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then the volatiles removed under reduced pressure. The residue was purified using silica gel chromatography, eluting with ethyl acetate containing 0-50% methanol, to give N-acetyl arginine methyl ester as a crystalline solid (2.53 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:6]([CH:15]=[CH2:16])[N:7]=1
Reactant: Nc1nc(Cl)nc(N2CCCCC2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc(N)nc(N2CCCCC2)n1
Temperature: 100 °C

Procedure:
To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL) was added tributyl(vinyl)tin (514 μL, 1.76 mmol) followed by Pd(PPh3)4 (97 mg, 0.084 mmol) and the reaction mixture was heated at 100° C. for 16 h in a sealed tube. Then, the reaction mixture was allowed to cool to room temperature, concentrated, and purified directly by flash chromatography on silica gel (AcOEt/hexane: 10/90→30/70) to afford the title compound 222 (containing tributyltin chloride).
Reaction SMILES: [Si]([O:18][C:19]1[CH:65]=[CH:64][C:22]([O:23][CH2:24][C@@H:25]([OH:63])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:55])=[CH:49][CH:48]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:57]([NH:56][C:54]([NH:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][CH2:45][C:37]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:63])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:65][CH:64]=4)=[CH:31][CH:32]=3)[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]=2)=[CH:48][CH:49]=1)=[O:55])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 89.5 %

Procedure:
N-[4-(2-{3-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}ethyl)phenyl]-N′-hexylurea (0.195 g, 0.220 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.128 g, 0.197 mmol).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][N:32]1C=CN=C1>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:31]#[N:32])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cn1ccnc1
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Product: COc1cccc(-c2c(C#N)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 160 °C
Reaction time: 21 h
Yield: 74.8 %

Procedure:
Alternatively, a mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (310 mg, 0.592 mmol) (Example 33), potassium ferrocyanide (50.0 mg, 0.118 mmol), copper(I) iodide (11.27 mg, 0.059 mmol) in 1-methylimidazole (3 mL, 37.6 mmol) was heated at 160° C. for 2 h. Extra potassium ferrocyanide (100 mg, 0.118 mmol) was added and heating continued at 160° C. for 21 h. The mixture was then cooled to RT. Purification by chromatography on silica gel, eluting with a gradient of 0-60% ethyl acetate in cyclohexane, afforded the title compound (208 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][C:11]([NH2:13])=[O:12])#[CH:2].Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1.F[B-](F)(F)F.CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:13][C:11](=[O:12])[CH2:10][C:4]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:19]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:15][N:16]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccc(F)cc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Temperature: 120 °C

Procedure:
A suspension of 2-(2-ethynyl-5-fluorophenyl)acetamide (A35) (0.114 g, 0.643 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.267 g, 0.585 mmol), PdCl2(PPh3)2 (0.021 g, 0.029 mmol), t-Bu3PH.BF4 (8 mg, 0.03 mmol) and CuI (6 mg, 0.03 mmol) in anhydrous DMF (4 mL) was degassed with nitrogen for 10 minutes. Et3N (1 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure, then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A36 as a yellow solid (0.198 g, 57%); 1H NMR (400 MHz, d6-DMSO) δ 10.41 (s, 1H), 8.81 (s, 1H), 7.69-7.62 (m, 3H), 7.47 (s, 1H), 7.31-7.19 (m, 4H), 7.07 (s, 1H), 4.05 (s, 2H), 3.72 (s, 2H), 2.80 (s, 2H), 2.69-2.59 (m, 1H), 1.74 (d, J=13.5 Hz, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.554 min; m/z 596 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:4]=1)#[CH:2].[CH2:24]([N:31]=[N+:32]=[N-:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(Cl)Cl.O>[CH2:24]([N:31]1[CH:2]=[C:1]([C:3]2[C:8]3[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:10][O:11][C:7]=3[C:6]([OH:18])=[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:4]=2)[N:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C(=O)OCC)c(O)c2onc(-c3ccccc3)c12
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
Ethyl 4-ethynyl-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (185 mg, 0.60 mmol), benzyl azide (0.087 mL, 0.66 mmol), CuSO4-5H2O (7.5 mg, 0.03 mmol), and sodium ascorbate (18 mg, 0.09 mmol) were added to a mixture of CH2Cl2 (2 mL) and water (2 mL). The mixture was stirred at room temperature for 16 h. Another equiv. of benzyl azide was added, and the mixture was stirred for an additional 16 h. The mixture was diluted with CH2Cl2 (20 mL) and water (20 mL). The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by flash chromatography (first with 0-100% EtOAc/hexanes, then with 0-50% CH2Cl2/EtOAc) to afford 100 mg of the title compound. MS: (+) m/z 442.33 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C1COCC1.[O:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[OH:25][C:22]1([CH:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[C:10]#[N:11])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: O=C1CCOCC1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC(c1ccc(C(F)(F)F)nc1)C1(O)CCOCC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 47.1 %

Procedure:
2-(6-(Trifluoromethyl)pyridin-3-yl)acetonitrile (260 mg, 1.4 mmol) was dissolved in THF (3 mL, 30 mmol) under Ar and cooled at −78° C. A solution of 0.6 Ni sodium bis(trimethylsilyl)amide in toluene (3.49 mL) was added dropwise. After stirring at −78° C. for 4 hours the reaction was allowed to reach −50° C. for 30 minutes. Then tetrahydro-4H-pyran-4-one (0.189 mL, 2.10 mmol) was added dropwise at −60° C. and the reaction was kept at this temperature for 45 minutes. To the reaction was added sat. aq. NH4Cl (10 mL) and it was extracted AcOEt (3×20 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to yield 2-(4-Hydroxytetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (189 mg, 0.660 mmol, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[O:12][C:10]2=O)=[CH:5][CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(C2CC(=O)OC2=O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(C2CC(=O)N(c3ccncc3)C2=O)cc1
Reaction time: 6.5 h

Procedure:
The starting material is prepared as follows: The mixture of 57.9 g of 2-(p-methoxyphenyl)-succinic anhydride, 26.3 g of 4-aminopyridine and 500 ml of xylene is refluxed on a water separator while stirring for 6.5 hours. The hot solution is decanted off, cooled, filtered and the residue recrystallized from ethanol, to yield the 3-(p-methoxyphenyl)-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 179°-180°; its 3,4-dimethoxy-analog melts at 172°14 174°.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:27]1([NH:30][C:31]([CH:33]2[O:38][CH2:37][CH2:36][NH:35][CH2:34]2)=[O:32])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:35]3[CH2:36][CH2:37][O:38][CH:33]([C:31]([NH:30][CH:27]4[CH2:28][CH2:29]4)=[O:32])[CH2:34]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)C1CNCCO1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 1 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.95 g, 2.35 mmol) was added to a solution of N-cyclopropylmorpholine-2-carboxamide (0.8 g, 2.6 mmol) (see following steps B and C for preparation) and DIPEA (0.82 mL, 4.7 mmol) in DCE (80 mL) at 80° C. The reaction mixture was stirred for 1 h and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 1.1 g (71%); 1H NMR (400 MHz, CDCl3) δ 0.39-0.54 (m, 2 H), 0.69-0.80 (m, 2 H), 1.49-1.69 (m, 3 H), 1.72 (s, 9 H), 1.75-1.86 (m, 3 H), 2.09 (t, J=10.84 Hz, 1 H), 2.2 (m, 3 H), 2.38-2.50 (m, 1 H), 2.61-2.71 (m, 1 H), 3.56 (d, J=11.91 Hz, 1 H), 3.67 (td, J=11.52, 1.95 Hz, 1 H), 3.91-4.06 (m, 3 H), 4.44 (d, J=7.03 Hz, 2 H), 6.58 (d, J=3.12 Hz, 1 H), 7.63-7.73 (m, 2 H), 8.04 (s, 1 H); MS (ESI) (M+H)+=538.8; Anal. Calcd for C26H36F2N4O4S+2.2 TFA: C, 46.25; H, 4.88; N, 7.10. Found: C, 46.26; H, 5.00; N, 6.95.
Reaction SMILES: CN(N=O)C(N[C@H:6]1[CH:11]([OH:12])[O:10][C@H:9]([CH2:13][OH:14])[C@@H:8]([OH:15])[C@@H:7]1[OH:16])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>>[O:14]=[CH:13][C@@H:9]([C@H:8]([C@@H:7]([C@@H:6]([CH2:11][OH:12])[OH:22])[OH:16])[OH:15])[OH:10]
Reactant: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
SD/IGS rats at 7 weeks of age (male, Charles River Laboratories Japan Inc.) were fasted for about 16 hours and then injected with 50 mg/kg streptozotocin (STZ) via the tail vein under ether anesthesia to prepare diabetic model rats. Similarly, another group of SD/IGS rats was injected with 1.25 mmol/L citric acid in physiological saline (1 mL/kg) via the tail vein under ether anesthesia to prepare normal control rats. At one week (8 weeks of age) after injection of STZ or 1.25 mmol/L citric acid in physiological saline, the rats were provided for an oral glucose tolerance test.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:21]1[O:28][C@H:27]([CH2:29]O)[C@@H:25]([OH:26])[C@H:23]([OH:24])[CH2:22]1.C(Br)(Br)(Br)[Br:39].CO>N1C=CC=CC=1>[Br:39][CH2:29][C@H:27]1[O:28][C@@H:21]([O:20][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22][C@@H:23]([OH:24])[C@@H:25]1[OH:26]
Reactant: BrC(Br)(Br)Br
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)C[C@@H](O)[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: O[C@H]1[C@H](O)C[C@H](OCc2ccccc2)O[C@@H]1CBr
Temperature: 50 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (4.5 g, 17.3 mmol, 2.2 eq) in pyridine (30 mL) was added dropwise to a cooled solution of Compound 1 (2.0 g, 7.9 mmol) and CBr4 (3.1 g, 9.4 mmol) in pyridine (30 mL) at zero degrees C. The mixture was then heated at 50° C. for 10 hours. After cooling, methanol (5 mL) was added dropwise, and the mixture was concentrated. The product was purified by flash column chromatography with CHCl3—MeOH (32:1) to give 1.82 g (yield 73 percent) of Compound 2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH:40]=[N:39]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cn(-c2ccc(-c3cnn(C(F)F)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol), 1-(difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester (122 mg, 0.50 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (183 mg, 85% yield) as a white solid: mp 185-187° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.41 (1H, t, J=8.3 Hz), 7.03-7.48 (10H, m), 7.79 (1H, d, J=1.9 Hz), 7.83 (1H, d, J=2.3 Hz), 7.91 (1H, d, J=0.8 Hz). LC-MS (ESI) m/z 479 [M+H]+. Anal. Calcd for C24H17F3N6O2: C, 60.25; H, 3.58; N, 17.57. Found: C, 60.19; H, 3.48; N, 17.52.