Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:26])[O:20][C@H:21]([CH2:23][CH2:24][CH3:25])[CH3:22].Br[C:28]1[N:29]=[C:30]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[CH2:40][CH2:39]2)[N:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=12>>[C:46]([NH:45][CH2:44][C@H:41]1[CH2:40][CH2:39][C@H:38]([C:30]2[N:31]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]3=[C:28]([C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:26])[O:20][C@H:21]([CH2:23][CH2:24][CH3:25])[CH3:22])=[C:3]([O:2][CH3:1])[CH:8]=3)[N:29]=2)[CH2:43][CH2:42]1)(=[O:48])[CH3:47]
Reactant: CCC[C@H](C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: CC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Product: CCC[C@H](C)OC(=O)Nc1ccc(-c2nc([C@H]3CC[C@H](CNC(C)=O)CC3)n3ccnc(C)c23)cc1OC

Procedure:
(S)-Pentan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-carbamate (20 mg) and N-(((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methyl)acetamide (20 mg) were reacted according to the procedure described in example 4 step 4c and purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give (S)-pentan-2-yl 4-(3-((trans)-4-(acetamidomethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate (16 mg).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:26][C:21]1[CH:22]=[N:23][N:24]=[CH:25][C:20]=1[CH2:19]2.C[Si]([N:31]=[C:32]=[N:33][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][C:3]2([CH2:26][C:21]4[CH:22]=[N:23][N:24]=[CH:25][C:20]=4[CH2:19]2)[C:2]3=[N:33][C:32]#[N:31])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4cnncc4C2)C3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cccc(C#N)c3)ccc2CC12Cc1cnncc1C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(1′-oxo-1′,3′,5,7-tetrahydrospiro[cyclopenta[d]pyridazine-6,2′-inden]-6′-yl)benzonitrile (0.0386 g, 0.11 mmol) in CH2Cl2 (5 mL) was added 0.5 mL of 1.0 M TiCl4 in CH2Cl2 at room temperature. After 1.5 h, 0.4 mL of bis(trimethylsilyl)carbodiimide was added to the yellow solution. The resulting mixture was then stirred at room temperature for 20 h. The mixture was quenched with ice, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=1.43 min in 3 min chromatography, m/z 362 (MH+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Sn](=O)CCCC)CCC.[N:51]([Si](C)(C)C)=[N+:52]=[N-:53].C1(C)C=CC=CC=1>C(OCC)(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:53][N:52]=[N:51][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 23.1 %

Procedure:
A mixture of 4′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.08 g), dibutyltin oxide (0.0037 g), azidotrimethylsilane (0.26 g) and toluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.02 g, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[N:30]=3)=[O:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (46 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 39 mg (31%). 1H-NMR: 8.64-8.61 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.03-6.99 (m, 2H), 6.91-6.88 (m, 2H), 3.75, s, 3H), 3.16 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.O>CS(C)=O>[CH3:14][C:9]1[C:10](=[O:13])[NH:11][CH2:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH3:18])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: CC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O
Reactant: Cc1ncc[nH]1
Solvent: O
Solvent: CS(C)=O
Product: CC1=C(c2ccc(-n3ccnc3C)c([N+](=O)[O-])c2)CNC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(4-Fluoro-3-nitrophenyl)-1,5-dihydro-3-methyl-2H-pyrrol-2-one (6.5g, 28 mmol) and 2-methylimidazole (6.8 g, 83 mmol) are combined in dimethylsulfoxide (50 mL) and the mixture is heated to 50° C. under a nitrogen atmosphere for 4 hr. The mixture is then cooled to room temperature, and water is added to give a precipitate. The mixture is kept cold for 1 hr, and the precipitate is collected by filtration, washed with water, and air-dried to provide the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:20]=1[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:21][C:20]=1[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1N1CCCC1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1N1CCCC1
Yield: 29.4 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (50 mg, 0.18 mmol), 1-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (60 mg, 0.2 mmol), potassium carbonate (63 mg, 0.46 mmol), Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.013 mmol), 1.4 mL dioxane and 0.3 mL water was stirred at 150° C. in a microwave for 30 min. The resulting mixture was treated with additional Pd(dppf)Cl2.CH2Cl2 (2 mg, 0.002 mmol), stirred at 160° C. in a microwave for 10 min, and partitioned between ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated to give a dark brown residue. The crude product was purified by preparative thin layer chromatography using 140:9.5:0.5 CH2Cl2:MeOH:conc NH4OH as eluant. The resultant brown solid was washed with CH2Cl2 and ethyl ether to provide 20 mg (29%) of 1-[2-(4-methoxy-3-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow solid. MP 211-213° C., M+H 379.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH:72]1([O:77][C:78]2[CH:83]=[CH:82][N:81]=[C:80]([Sn](CCCC)(CCCC)CCCC)[CH:79]=2)[CH2:76][CH2:75][CH2:74][CH2:73]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:80]4[CH:79]=[C:78]([O:77][CH:72]5[CH2:76][CH2:75][CH2:74][CH2:73]5)[CH:83]=[CH:82][N:81]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC2CCCC2)ccn1
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(OC4CCCC4)ccn3)nc12)C(=O)N1CCC(C#N)CC1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-cyclopentyloxy-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=530.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22]C[C:20](=[O:23])[CH2:19][CH2:18]2)[CH:9]=1.NC1N2N=CC=C2N=C(C2CCC(=O)C2)C=1.NC1N2N=CC=C2N=C(C2CCC(=O)CC2)C=1>>[CH3:29][Si:28]([CH3:30])([CH3:31])[CH2:27][CH2:26][O:25][CH2:24][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:32])([CH3:1])[CH3:33])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:22]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: Nc1cc(C2CCC(=O)C2)nc2ccnn12
Agent: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)C2)nc2ccnn12

Procedure:
3-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentanone was synthesized in a manner similar to the synthesis of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone, but 3-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclopentanone substituted for 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH3:14]
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)CNCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN(Cc1ccccc1)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a solution of ethyl N-benzyl-glycinate (34.1 g, 176 mmol) and m-anisaldehyde (11.0 g, 80.8 mmol) in methanol (500 mL) was added acetic acid (12.1 mL, 202 mmol) followed by sodium cyanoborohydride (3.4 g, 54 mmol). The mixture was stirred at ambient temperature for 2.5 hours whereupon LCMS analysis showed completion of the reaction. The solvent was removed on a rotary evaporator and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate to neutrality. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (CH2Cl2) gave 21.5 g (85% of [benzyl-(3-methoxy-benzyl)-amino]-acetic acid ethyl ester as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (m, 4H), 7.25 (m, 2H), 6.93 (m, 2H), 6.82 (d, J=9 Hz, 1H), 4.10 (q, J=7 Hz, 2H), 3.74 (s, 3H), 3.70 (s, 2H), 3.32 (s, 2H), 3.24 (s, 2H), 1.18 (t, J=7 Hz, 3H; MS (m/e) 314 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39]O)[CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(Cl)Cl.O>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:32]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccnc1
Reaction time: 2 h

Procedure:
Cool a mixture of phthalimide (5.4 g, 37 mmol) and PPh3 (9.6 g, 37 mmol) in tetrahydrofuran (80 mL) to 0° C. Add dropwise a solution of 3-pyridine propanol (5.0 g, 37 mmol) and diethyl azodicarboxylate (5.8 mL, 37 mmol) in tetrahydrofuran (50 mL). After 2 hours, dilute the reaction mixture with methylene chloride (100 mL), and water (100 mL). Wash the organic layer with water (100 mL), then brine (100 mL). Dry over magnesium sulfate, filter and concentrate to afford 2-(3-pyridin-3-yl-propyl)isoindole-1,3-dione as a yellow solid which can be used without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.C(OCC)(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:18][CH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:19])[NH:9][CH:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)C(Cc1ccccc1)NC2=O
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NCc1ccc2c(c1)C(Cc1ccccc1)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a solution of 3-benzyl-1-oxoisoindoline-5-carbonitrile (190 mg, 0.77 mmol) in MeOH (4 mL) was added cobalt(II) chloride hexahydrate (364 mg, 1.53 mmol), then added NaBH4(232 mg, 6.12 mmol) in portions carefully within 45 min. The reaction mixture was stirred at room temperature for 30 min, TLC showed complete conversion. Carefully quenched reaction by adding concentrated HCl until the black precipitates dissolved. The reaction mixture was basified with concentrated NH4OH until pH=8-9, a brown colour slurry was obtained, diluted with ethyl acetate. This was filtered, for filtrate, washed 1× with water. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 5-10% MeOH in dichloromethane (0.5% NEt3 added), 80 mg (41%) of the product was obtained.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]O)[OH:19])[CH3:9].C(N(CC)CC)C.[Cl-].[Li+].CS([Cl:44])(=O)=O>CN(C)C=O.O>[Cl:44][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][S:21][CH2:20][C:11]1([OH:19])[CH2:12][CH2:13][CH:14]([OH:18])[CH:15]([O:16][CH3:17])[CH:10]1[C:2]1([CH3:9])[O:1][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC1C(O)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Yield: 67 %

Procedure:
In dimethylformamide (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4cyclohexanediol (100 mg) and triethylamine (64 μl). To the solution was added, under ice-cooling, lithium chloride (21 mg). To the mixture was added dropwise methanesulfonyl chloride (20 μl), which was stirred for hours, then the reaction was suspended by the addition of water. The product was extracted with ether, and the extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : ethyl acetate - hexane=1:2) to give 1-(2-chloromethylbenzyl)thiomethyl-2 -(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (70 mg: yield 67%) as a colorless oily product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl.[CH:9]12[CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:9]12[CH2:14][CH:13]1[CH2:12][N:11]([C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1)[CH2:10]2
Reactant: Brc1csc(Br)n1
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1csc(N2CC3CC3C2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a stirred solution of 2,4-dibromothiazole (0.5 g. 2.06 mmol) in DMF (15 ml) were added 3-azabicyclo[3.1.0]hexane hydrochloride (prepared according to the procedure given in Bioorganic and Medicinal Chemistry Letters, 2005, 15, 2093-2096, 0.27 g, 2.26 mmol) and DIPEA (0.80 g, 1.0 ml, 6.17 mmol) under a stream of nitrogen. The reaction was then stirred at 80° C. for 18 hrs; the progress of reaction was monitored by TLC. The reaction was quenched with cold water (20 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with water (2×10 ml), dried over sodium sulphate and concentrated to give crude compound; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.29 g, 58.5%). MS: m/z 246 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:18]([CH3:19])[CH3:17])=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c(S(C)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
To a stirred solution of 5.23 g (22.5 mmol) 4-Fluoro-3-methanesulfonyl-benzoic acid methyl ester (J. Med. Chem.; 40; 13; 1997; 2017-2034) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 7 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 10a was obtained in 56% yield (3.24 g, 12.6 mmol).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:18].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[Cl:1][CH2:2][C:3]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:18])=[O:4]
Reactant: Nc1ccc2ccccc2c1O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C(CCl)Nc1ccc2ccccc2c1O
Temperature: 15 °C
Yield: 59.8 %

Procedure:
2 ml of chloroacetyl chloride (25.4 mmol) were added dropwise to a suspension of 5 g of 2-amino-1-naphthol hydrochloride (25.4 mmol) and 5.08 g of calcium carbonate in 200 ml of dioxane, with stirring and under an inert atmosphere. The reaction medium was stirred at 40° C. for 1 hour 30 minutes, cooled to 15° C., filtered on sintered glass and the inorganic salts were rinsed twice with ethyl acetate. The combined organic phases were concentrated until an insoluble product appeared. The concentrate was poured over 250 ml of ice-cold water. The precipitate formed was drained, washed with water and dried under vacuum to a constant weight to give 3.58 g of 2-chloro-N-(1-hydroxynaphthalen-2-yl)acetamide in the form of a beige powder with a yield of 60%.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl[C:27]1[N:32]=[CH:31][C:30]([O:33][C:34]2[C:39]([C:40]3[CH:45]=[CH:44][N:43]=[C:42]([S:46][CH3:47])[N:41]=3)=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:29][CH:28]=1.C[Si]([N-:52][Si](C)(C)C)(C)C.[Li+]>O1CCOCC1.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]>[CH3:47][S:46][C:42]1[N:41]=[C:40]([C:39]2[C:34]([O:33][C:30]3[CH:29]=[CH:28][C:27]([NH2:52])=[N:32][CH:31]=3)=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:45]=[CH:44][N:43]=1
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(Cl)nc2)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Solvent: C1COCCO1
Product: CSc1nccc(-c2cccnc2Oc2ccc(N)nc2)n1
Temperature: 65 °C

Procedure:
To a brown solution of tris(dibenzylideneacetone)dipalladium (o) (0.68 g, 0.75 mmol), 2-(dicyclohexylphosphino)biphenyl (0.50 g, 1.4 mmol), and 4-(2-(6-chloropyridin-3-yloxy) pyridin-3-yl)-2-(methylthio)pyrimidine (1.9 g, 5.7 mmol) in 15 mL dioxane was added solid lithium bis(trimethylsilyl) amide (2.9 g, 17 mmol). Argon was bubbled through the reaction for 1 min, and then it was sealed and heated to 65° C. for 3.5 days. The reaction was cooled to ambient temperature, diluted with water, and acidified to a pH of about 1 with stirring, then brought to pH of about 5 with 6N NaOH. Dichloromethane was added and reaction was filtered through 2 cm Celite® in a frit, rinsing with MC and water. The layers were separated, and the organic layer was dried over anhyd. Na2SO4, filtered, and concentrated in vacuo. The material was diluted in 100 mL MC, and extracted 3×100 mL 1 N HCl. The aqueous layers were cooled to 0° C. and basified with 6 N NaOH to about pH of 10. The aqueous layer was extracted 3×100 mL with MC. The organic layers were combined, dried over anhdrous sodium sulfate, filtered, and concentrated in vacuo to a brown oil. The oil residue was purified by silica gel chromatography, 120 g, 0-50% MC-90/10 MC/MeOH, to afford 5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine as a yellow solid. MS m/z=312 [M+H]+. Calc'd for C15H13N5OS: 311.4.