Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[C:35](=[O:36])[C:34]([CH3:38])([CH3:37])[NH:33][C:32]2=[O:39])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[C:34]([CH3:37])([CH3:38])[C:35](=[O:36])[N:31]([CH2:30][C:29]5[CH:40]=[CH:41][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:39])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: COc1ccc(CN2C(=O)NC(C)(C)C2=O)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C(C)(C)C2=O)cc1

Procedure:
To a mixture of (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165, 3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (119 mg) described in Preparation Example 53, cesium carbonate (260 mg) and copper(I) iodide (38 mg) were added toluene (8 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was stirred with heating under reflux for 29 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione. The obtained 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione was dissolved in 1,2-dichloroethane (4 mL), trifluoromethanesulfonic acid (92 μL) was added and the mixture was stirred at 80° C. for 13 hr. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform/methanol (10:1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (34 mg).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[CH:23][CH:22]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CCNC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(4-amino-phenyl)-ethylamine and DIEA to give 2-[2-(4-amino-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 375 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]4)=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(OCC4CC4)cc3)ccc2[nH]1
Yield: 72.3 %

Procedure:
A solution of 4-(cyclopropylmethoxy)benzoic acid (576 mg), ethyl 5-amino-1H-indole-2-carboxylate (612 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (690 mg), 1-hydroxybenzotriazole (551 mg) and N,N-dimethylaminopyridine (367 mg) in DMF (20 mL) was stirred at room temperature for 2 hr. The reaction solution was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue (brown solid) was washed with a small amount of ethyl acetate to give the title compound (820 mg, yield 72%).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]Cl.[Na+].CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>CCOC(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
5 g (27.17 moles) of diphenyl-methanol dissolved in 55 ml of AcOEt (RPE Carlo Erba) were added to 177 ml of a commercial solution (RPE Carlo Erba) of NaOCl (about 271.7 moles) containing 1.65 g (about 4.1 moles) of Aliquat-336.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH:7][C@H:8]([C:10]1[C:11]([CH3:15])=[N:12][NH:13][CH:14]=1)[CH3:9])=[O:6])([CH3:4])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=N1>CN(C=O)C.CCOC(C)=O.CCOC(C)=O.CCCCCCC>[CH2:22]([N:13]1[CH:14]=[C:10]([C@@H:8]([NH:7][S@@:5]([C:2]([CH3:3])([CH3:4])[CH3:1])=[O:6])[CH3:9])[C:11]([CH3:15])=[N:12]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1n[nH]cc1[C@H](C)N[S@](=O)C(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cn[nH]c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: Cc1nn(Cc2ccccc2)cc1[C@H](C)N[S@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
(R)-2-methyl-N—((S)-1-(3-methyl-1H-pyrazol-4-yl)ethyl)propane-2-sulfinamide (290 mg, 1.26 mmol) was dissolved in DMF (5 ml) and added dropwise to a solution of Cs2CO3 (458 mg, 1.41 mmol) in DMF (4 ml). The resulting reaction mixture was stirred at room temperature for 15 min. benzylbromide (216 mg, 1.26 mmol) was added and the reaction was stirred at room temperature for 2 h. LCMS shows mostly product with some starting pyrazole. Added another 0.1 ml of BnBr and 135 mg of Cs2CO3. Stirred another 24H at 50° C. The reaction mixture was diluted with EtOAc (300 mL), washed with 4% aqueous NaCl (2×150, 2×50 mL). The combined aq. layers were back extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. Silica gel chromatography, EtOAc/heptane 20-80% to give title compound (mix of regioisomers, 150 mg, 0.470 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:12])[CH:7](Br)[CH2:8][CH2:9][CH3:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][SH:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCC.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:12])[CH:7]([S:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(Br)C(=O)N[C@@H](CCc1ccccc1)C(=O)OC
Reactant: COc1ccc(CS)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)OC
Reaction time: 15 h

Procedure:
Combine 2-bromopentanoyl-(L)-homophenylalanine methyl ester (3.6 g, 10 mmol), 4-methyoxybenzylmercaptan (3.48 mL, 25 mmol), and tetrabutylammonium iodide (about 50 mg) in dimethylformamide (10 mL). Degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add cesium carbonate (4.10 g, 12.5 mmol). After 15 hours, partition the reaction mixture between water and methyl t-butyl ether, saturate the aqueous layer with sodium chloride. Extract the aqueous layer with brine, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 4/1 hexane/ethyl acetate and then 2.5/1 hexane/ethyl acetate to give the title compound: Rf=0.44 (silica gel, 2.5/1 hexane/ethyl acetate).
Reaction SMILES: O.[CH:2]1[C:7](N=C=S)=[CH:6][C:5]2[C:11]([O:13][C:14]3([C:24]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=4[O:22][C:16]4[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]3=4)[C:4]=2[CH:3]=1)=[O:12]>O1CCCC1>[CH:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([C:14]2[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[O:22][C:23]3[C:24]=2[CH:25]=[CH:26][C:27]([CH:28]=3)=[O:29])[CH:3]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 1.05 h

Procedure:
A PNA or PNA derivative having a single free NH2 such as H2N-GCAT-COOH is dissolved in tetrahydrofuran:water to provide a solution that is 0.1 M in PNA and to this is added fluorescein isothiocyanate to give a solution which is 0.1-1.0 M in fluorescein isothiocyanate. The solution is. stirred for 0.1-2 hours, then evaporated to a solid and purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCC=CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl p-aminocinnamate, one equivalent of 1-bromohexadecene, one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:1 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled, filtered and the precipitate is washed with water. Recrystallization from chloroform yields 4-hexadecylaminocinnamic acid.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN2c3ccccc3Cn3cccc3C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred solution of 1.3 g of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (Example 4) and 550 mg of triethylamine in 15 ml of tetrahydrofuran is added 765 mg of benzoyl chloride. After allowing the mixture to stir at room temperature overnight it is evaporated and the residue taken up in 100 ml of water. The mixture is extracted with diethyl ether, washed successively with water and brine, dried and evaporated, to yield 2-benzoyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 137°-139° after recrystallization from isopropanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10]1[CH2:20][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>C1COCC1.CCOCC>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][CH2:20][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCCc2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(C2=CCCc3ccccc32)c1
Reaction time: 8 h

Procedure:
A solution of the Grignard reagant derived from 50 g (0.27 mol) of 3-bromoanisole in 200 ml of dry THF was treated with a solution of alpha-tetralone in 100 ml of THF added over 1 hour while maintaining the internal temperature at 15°-25° C. After stirring overnight, the mixture was diluted with 500 ml of ether and quenched with 200 ml of 20% aqueous ammonium chloride. The aqueous layer was extracted with 200 ml of ether. The combined organic layers were dried over MgSO4 and evaporated to 66.5 g of the oily alcohol. This was dissolved in 450 ml of dry toluene containing 0.020 g of p-toluenesulfonic acid and refluxed overnight in a Dean-Stark apparatus. After cooling, the mixture was washed with 100 ml of 5% sodium bicarbonate, with 100 ml of water, and then with 100 ml of brine. The mixture was dried over MgSO4 and evaporated. The residue was distilled under reduced pressure to give the title compound, b.p. (0.5 mm) 158°-162° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:17]1[CH:21]2[CH2:22][C:23](=[O:24])[CH:19]([CH2:20]2)[CH2:18]1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[OH:24][C:23]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH2:22][CH:21]2[CH2:20][CH:19]1[CH2:18][CH2:17]2
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=C1CC2CCC1C2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2(O)CC3CCC2C3)cc1
Temperature: -47 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-iodobenzoate (23.1 g, 0.0882 mol) dissolved in anhydrous THF (200 mL) was cooled to −47° C. Isopropyl magnesium chloride (48 mL of a 2.0 M solution in THF, 0.097 mol) was slowly added to the solution. The reaction mixture was stirred at −47° C. for 1 h, then cannulated into a pre-cooled solution of norcamphor (11.6 g, 0.105 mol) in THF (100 mL) at −47° C. The reaction mixture was subsequently stirred at −40° C. overnight, and was then allowed to warm to −20° C. Saturated aqueous ammonium chloride was added. EtOAc was used to extract three times. The combined organic portion was washed with water and brine, dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (gradient elution; 0%-30% EtOAc/hexanes as eluent) to afford the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(I)c1
Reactant: N#Cc1ccc(B(O)O)cc1
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: C1COCCO1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(-c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-iodo-4-methylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (103 mg,0.247 mmol) and 4-cyanophenylboronic acid (55 mg, 0.371 mmol) in 4 ml of 1,4-dioxane stirring under nitrogen was treated with 2M sodium carbonate (0.37 mL, 0.741 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.6 mg, 0.011 mmol). This was refluxed for three hours and then allowed to stir at room temperature for 16 hours. The reaction had not completed after this time so the reaction was treated with an additional 5.7 mg(0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) and refluxed for two hours. The reaction was then cooled to room temperature and concentrated in vacuo. This was then dissolved in a minimal amount of dichloromethane and purified on a Chromatotron (200 omicron plate) with 3% methanol/dichloromethane to give a residue which was recrystallized using ether/hexanes to give the title compound. 1H NMR: 8.45-8.55 (d, 1H, J=4 Hz), 8.35-8.40 (s, 1H), 7.75-7.80 (d, 1H, J=12 Hz), 7.65-7.70 (d, 1H, J=12 Hz), 7.20-7.35 (m, 5H), 7.15-7.20 (m, 1H), 7.00-7.05 (s, 1H), 4.85-4.95 (s, 2H), 3.05-3.15 (q, 2H, J=10z), 2.15-2.20 (s, 3H), 1.40-1.50 (t, 3H, J=8 Hz); MS calcd. 391.5; MS (M+1)=392.1.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH2:37][CH:36]([N:35]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:32])[F:33])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH3:34])[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and tert-butyl 4-(methylamino)piperidine-1-carboxylate following General Procedure B.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[N:10]([CH3:21])[CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH:19]=[O:20])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([O:8][C:9](=[O:22])[N:10]([CH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17]1)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](CC=O)CC1)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CCO)CC1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A stirred solution of 0.75 g (2.47 mmol) trans-methyl-[4-(2-oxo-ethyl)-cyclohexylmethyl]-carbamic acid benzyl ester in 15 ml of methanol was cooled to 0-5° C. 0.14 g (3.7 mmol) of sodium borohydride were added in four equal portions, at intervals of 10 minutes. Stirring was continued for 1 hour at room temperature. Afterwards, a 1N aqueous hydrochloric acid solution was dropped into the solution until the medium was acidic; it was then made neutral by addition of aqueous sodium bicarbonate solution. The reaction mixture was subsequently extracted 3 times with 25 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on silica gel with a 95:5 v/v mixture of dichloromethane and methanol as the eluent. 0.63 g (83%) trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid benzyl ester were obtained as colorless oil, MS: 306 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143–146° C.; 1H NMR (300 MHz, CDCl3): δ 7.15 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 7.03 (s, 1 H), 4.94–4.90 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.7, 3.3 Hz, 1 H), 3.33 (s, 3 H), 3.10 (t, J=8.1 Hz, 2 H), 1.88–1.70 (m, 2 H), 0.91 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Cl3 (M+H)+: 402.0543; found m/z 402.0568.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19](Br)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncccc2Br)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ncccc2N2CCc3ccccc32)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 35.4 %

Procedure:
A mixture of 3-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (94) (280 mg, 0.82 mmol), 2,3-dihydro-1H-indole (97 mg, 0.82 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), BINAP (24 mg, 0.04 mmol) and t-BuONa (173 mg, 1.64 mmol) in toluene (20 mL) was stirred at 100° C. for 12 h. The mixture was left to reach RT and filtered through a pad of Celite and the filter cake was washed with CH2Cl2 (30 mL). The combine filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (20% to 40% EtOAc in petroleum ether) to afford 3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (95) (100 mg, 0.29 mmol, yield 32%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].[NH2:12][C:13]1[C:18]([C:19]#[N:20])=[C:17](F)[CH:16]=[CH:15][CH:14]=1.O>CN1C(=O)CCC1>[NH2:12][C:13]1[C:18]([C:19]#[N:20])=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1c(N)cccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4-(Hydroxyethyl)morpholine (1.02 eq) was added to NaH (1.2 eq) in NMP. After 10 minutes, 6-amino-2-fluorobenzenecarbonitrile (1.0 eq) was added in NMP. The resulting mixture was heated at 100° C. for 1 hour. The mixture was then cooled and poured into H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yield a brown gum. The crude material was purified by silica gel chromatography (5:1:95 MeOH:Et3N:EtOAc) to give the desired product. LC/MS m/z 248.3 (MH+), Rt 1.26 minutes.