Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[CH2:11]=[C:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:12]1([CH3:11])[CH:13]2[CH2:21][CH:17]3[CH2:16][CH:15]([CH2:20][CH:19]1[CH2:18]3)[CH2:14]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=C1C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 36.0 g (0.50 mol) of acrylic acid, 0.5 g (5 mmol) of sulfuric acid and 100 g of toluene. Separately 88.8 g (0.60 mol) of 2-methyleneadamantane, prepared by the same procedures as described in Reference Example 1, was dissolved in 100 g of toluene. The obtained solution of 2-methyleneadamantane in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 20° C. Then the content was stirred for 5 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 100.7 g (yield: 91.5%) of the object 2-methyl-2-adamantyl acrylate was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].[Si:10]([O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[NH:34][C:35](=[O:44])[C:36]2[CH:41]=[C:40](I)[CH:39]=[CH:38][C:37]=2[F:43])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CC#N.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>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:40]2[CH:39]=[CH:38][C:37]([F:43])=[C:36]([CH:41]=2)[C:35]([NH:34][C:25]2[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:24]=2[N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([O:17][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH2:19]2)=[O:44])=[CH:4][N:5]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reactant: C#Cc1cnc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Temperature: 70 °C

Procedure:
In a 16×120 mm resealable pyrex tube, 5-ethynylpyrimidin-2-amine (0.080 g, 0.67 mmol), (R)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide (0.210 g, 0.34 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.017 mmol), and Copper(I) iodide (0.0032 g, 0.017 mmol) were taken up in CH3CN and Triethylamine (0.71 ml, 5.1 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70° C. overnight. The reaction was cooled, and transferred to a 50 mL RBF with EtOAc. The mixture was concentrated in vacuo, and the resulting solid was treated with 10% MeOH in CH2Cl2 and adsorbed onto 1.5 g silica gel and passed through a Redi-Sep®D pre-packed silica gel column (40 g) eluting with 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide as an off-white solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:1]([CH2:8][CH2:9][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCOc2ccccc2)CC1)c1ccccc1

Procedure:
2-Phenoxyethylbromide (2.01 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were reacted together according tothe procedure of Example 51. The title compound as its hydrochloride (2.06 g.) had m.p. 207° C. (Found: C, 67.0; H, 7.1; N, 7.7. C20H24N2O2.HCl requires C, 67.3; H, 7.1; N, 7.85%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:19]4[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:30])[CH2:32][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(C1CCN(c2cc(Cl)ncn2)CC1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
4-Trifluoromethylphenylsulphonyl chloride (1.32 g) was added to a mixture 1-[1-(6-chloro-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine hydrochloride (2.60 g) and triethylamine (5.00 ml) in dichloromethane (100 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1.5% methanol in dichloromethane to give 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(6-chloro-pyrimidin-4-yl)-4-piperidylcarbonyl]piperazine (1.80 g) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[CH:12][CH3:13]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC=COc1ccccc1[N+](=O)[O-]
Yield: 91.9 %

Procedure:
2-Nitrophenol (142.0 g, 1.02 mole), allyl bromide (120.9 g, 1.00 mole), anhydrous potassium carbonate (140.0 g, 1.02 mole) and dry acetone (500 cc) were refluxed for 21 hours, and filtered to remove the potassium bromide. The residue was washed with acetone and the solvent was removed by rotary evaporation. The residue was partitioned between 200 cc of dichloromethane and water. The dichloromethane layer was washed with 200 cc of 10% potassium hydroxide, separated and the solvent was removed by rotary evaporation. The crude product was fractionally distilled at 124° C. at 2.0 mm. Hg to yield 164.7 g of product (91.9%).
Reaction SMILES: ClCS(Br)(=O)=O.O1CC=CC1.C(OO)(C)(C)C.[Cl:18][CH2:19][S:20]([CH:23]1[CH:27](Br)[CH2:26][O:25][CH2:24]1)(=[O:22])=[O:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:18][CH2:19][S:20]([C:23]1[CH2:24][O:25][CH2:26][CH:27]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(CCl)C1COCC1Br
Agent: C1=CCOC1
Agent: CC(C)(C)OO
Agent: O=S(=O)(Br)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(CCl)C1=CCOC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
19.3 g (0.1 mole) of chloromethanesulfonic acid bromide are added in the course of 10 minutes to a solution of 14 g (0.2 mole) of 2,5-dihydrofuran and 0.5 ml of tert.-butyl hydroperoxide in 30 ml of chloroform at -40° C. After 15 minutes, 16.5 ml of triethylamine, dissolved in 20 ml of chloroform, are added dropwise at the same temperature, so as to dehydrobrominate the 3-chloromethylsulfonyl-4-bromotetrahydrofuran which has been formed. The mixture is stirred for half an hour at 20° C., washed with water, dried and concentrated. The residue is repeatedly digested with ether and the ether extract is distilled; it boils at 115°-120° C./0.2 mm Hg. 4.8 g of 3-chloromethylsulfonyl-2,5-dihydrofuran are obtained.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C@H:10]1[CH2:14][O:13][S:12](=[O:15])[N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+].O.CCOC(C)=O>CC#N.O.[Ru](Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=1)[C@H:10]1[CH2:14][O:13][S:12](=[O:34])(=[O:15])[N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1(=O)=O
Yield: 94.2 %

Procedure:
A mixture of tert-butyl (4R)-4-((S)-((tert-butyl(dimethyl)silyl)oxy)(4-(trifluoromethyl)phenyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (1.80 g, 3.63 mmol), sodium periodate (3.11 g, 14.5 mmol), ruthenium(III) chloride hydrate (0.0164 g, 0.0726 mmol) in CH3CN:water:EtOAc (51 mL:17 mL:9 mL) was put in a sonicator for 17 minutes. The dark mixture became a yellow suspension. HPLC-MS showed no more starting material. The reaction mixture was filtered through celite and the solid was washed with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-4%-10% EtOAc-hexane) to provide the product as a white solid (1.75 g, 94%). LCMS (API-ES) m/z: 456 (M+H+-56).
Reaction SMILES: [CH3:1][Li].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1>C1COCC1>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:15])[CH3:1])=[N:5]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1nn(C)c2ccccc12

Procedure:
Methyl lithium (1.58M solution in ether; 13.8 ml) was added dropwise to a stirred, cold (-60°) solution of 1-methyl-1H-indazole-3-carboxylic acid (1.77 g) in dry THF (60 ml) under nitrogen and stirring was continued while warming to 0° over 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml), and the layers were separated. The aqueous layer was further extracted with dichloromethane (2×50 ml) and the combined organic layers were washed with brine (2×50 ml), dried and evaporated in vacuo. The residual solid (1.8 g) was purified by FCC eluting with System B (1:4) to give the title compound (1.3 g), m.p. 86°-88°.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:27]([OH:29])=[O:28])(O)=[O:2].FC1C=C2[C:37](=CC=1)[N:36](CC1C3C(=CC=C(F)C=3)C=CC=1)[C:35]1C(=O)OC(=O)CC2=1.CNC>>[CH3:35][N:36]([CH3:37])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:27]([OH:29])=[O:28])=[O:2]
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccc(F)cc12
Reactant: O=C1Cc2c(n(Cc3cccc4ccc(F)cc34)c3ccc(F)cc23)C(=O)O1
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
3-Carboxymethyl-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (from Example 97) was converted to 6-fluoro-9-(7-fluoro-naphthalen-1-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was converted according to Example 68.2. but using dimethyl amine to give the title compound as a white solid. MS: 421.0 ([M−H]−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[CH:3]=1>C(N)C(C)C>[CH3:10][CH:11]([CH3:2])[CH2:6][NH:5][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[CH:3]=1
Reactant: Clc1cc2nnnn2c2cnccc12
Solvent: CC(C)CN
Product: CC(C)CNc1cc2nnnn2c2cnccc12

Procedure:
A suspension of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine (20 g) in isobutylamine (100 mL) was heated at reflux for several hours. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane, washed with water, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from toluene to give a material that was a mixture by thin layer chromatography. The material was purified by flash chromatography, silica gel eluting with dichloromethane, 5-20% ethyl acetate in dichloromethane, and 10% methanol in dichloromethane. The fractions with the slower moving material were concentrated to provide N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine as a solid, m.p. 220-221° C. Analysis: Calculated for C12H14N6: %C, 59.49; %H, 5.82; %N, 34.69; Found: %C, 59.35; %H, 5.89; %N, 34.88.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: Oc1c(F)cccc1F
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,6-difluorophenol (25 g), potassium carbonate (39.5 g) and acetone (100 ml) was added dropwise with stirring at room temperature a solution of methyl bromoacetate (17.8 ml) in acetone (100 ml). After stirring at room temperature overnight, the reaction mixture was taken up in a mixture of conc. hydrochloric acid (40 ml) and ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave methyl 2,6-difluorophenoxyacetate (38 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](Cl)=[O:13])[CH2:4][CH2:3]1.[Mg].[CH2:17](Br)[CH3:18]>CCOCC.[Cu]I>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:13])[CH2:17][CH3:18])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C(=O)Cl)c2ccccc21
Reactant: CCBr
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Reaction time: 5 h
Yield: 64 %

Procedure:
223 g (1 mol) of 1,1-dimethyl-tetralin-4-carboxylic acid chloride and 11 g of copper (I) iodide are placed in a 1-liter flask provided with a thermometer, stirrer, dropping funnel and reflux condenser and there is allowed to drop in from the dropping funnel at -10° C. to -5° C. a Grignard solution freshly prepared from 27 g (1.1 mol) of magnesium shavings and 122 (1.12 mol) of ethyl bromide in 500 ml of absolute ether. In so doing, the mixture must be diluted with a small amount of ether. The mixture is stirred for a further 5 hours while cooling and then the cooling source is removed. After the mixture has reached room temperature, it is poured into cold, saturated ammonium chloride solution, extracted with ether, washed neutral with water, dried over sodium sulphate and evaporated. Fractional distillation gives 138 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 64%. Ventilation can further improve the olfactory quality. Odour: see (3).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:2]([NH:1][CH:4]4[CH2:5][CH2:6][CH:7]([C:10]([F:11])([F:12])[F:13])[CH2:8][CH2:9]4)=[O:3])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: O=C=NC1CCC(C(F)(F)F)CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCC(C(F)(F)F)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-isocyanato-4-(trifluoromethyl)cyclohexane, and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=518.2.
Reaction SMILES: [Cl:1]CC[CH:4]([S:10][CH:11]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)CCCl)[C:5]1OC=CC=1.O.C(Cl)(Cl)Cl.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[ClH:1].[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH2:11][S:10][CH2:4][CH2:5][NH:28][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: ClCCC(SC(CCCl)c1ccco1)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)NCCSCc1ccco1
Product: Cl

Procedure:
A solution of 2-chloroethyl-2-furanylmethyl sulfide in isopropylamine is agitated 8-12 hr in a stainless steel bomb at 80° C. The reaction mixture is then stripped to dryness and the residue is partitioned between water and chloroform. The chloroform layer is extracted with 1N sulfuric acid; whereupon two layers are obtained: a water phase (upper), and a chloroform phase (lower). The aqueous phase is made alkaline and extracted with chloroform. Evaporation of the organic layer yields the free base of the title compound, which is reacted with ethereal hydrogen chloride to give the hydrochloride salt which is then recrystallized from methanol/diethyl ether.
Reaction SMILES: [OH:1][CH:2]([CH:5]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11](=[O:16])[NH:10]1)[CH2:3][OH:4].[C:25](Cl)(Cl)=[O:26]>>[O:16]=[C:11]1[NH:10][CH:9]([CH2:8][CH2:7][CH2:6][CH:5]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH:2]2[CH2:3][O:4][C:25](=[O:26])[O:1]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(CCCC1CCCCC(=O)N1)C(O)CO
Product: CC(C)(C)OC(=O)NC(CCCC1CCCCC(=O)N1)C1COC(=O)O1

Procedure:
The product of EXAMPLE 269 is reacted with phosgene by the method of EXAMPLE 261, to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25](OC)=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:29]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25]([NH2:29])=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Reactant: N
Solvent: CO
Product: Cl
Product: NC(=O)Cc1cccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Yield: 86 %

Procedure:
Following general procedure C, methyl 2-(3-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.090 g, 0.23 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL), followed by formation of the hydrochloride salt to afford the title compound (0.082 g, 86%) as a light yellow solid. MW=414.33. 1H NMR (DMSO-d6, 500 MHz) δ 14.13 (s, 1H), 9.87 (s, 1H), 7.94 (t, J=1.8 Hz, 1H), 7.79-7.74 (m, 1H), 7.68-7.64 (m, 1H), 7.63-7.54 (m, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.36-7.35 (m, 1H), 7.30-7.25 (m, 1H), 7.24-7.18 (m, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 3.45 (s, 2H), 3.17 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 378 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCCCCC.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][N:20]([C:26]2[N:31]=[CH:30][C:29]([C:2]3[N:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:3]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:22]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cc(N2CCOCC2)ncc1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1.[CH:13]1[C:22]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:14]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:69]CC2C=CC=CC=2)=[C:28]([C@@H:30]2[O:59][C@H:58]([CH2:60][O:61]CC3C=CC=CC=3)[C@@H:49]([O:50]CC3C=CC=CC=3)[C@H:40]([O:41]CC3C=CC=CC=3)[C@H:31]2[O:32]CC2C=CC=CC=2)[CH:29]=1.O>C(Cl)Cl>[CH:13]1[C:22]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:14]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:69])=[C:28]([C@@H:30]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:49]([OH:50])[C@H:40]([OH:41])[C@H:31]2[OH:32])[CH:29]=1
Reactant: c1ccc(COC[C@H]2O[C@@H](c3cc(Cc4cc5cccccc-5c4)ccc3OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2cc(Cc3cc4cccccc-4c3)ccc2O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
Aluminum chloride (0.12 g) and anisole (4.0 ml) were added to a solution of (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (0.07 g) in methylene chloride (5 ml) and the mixture was stirred at room temperature for two hours. The reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol (0.01 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH:11]=O)=[C:8]([CH3:13])[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:29][CH:30]=[CH:31][N:32]=2)=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:58]>>[ClH:58].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([N:33]3[CH2:34][CH2:35][N:36]([CH2:11][CH2:10][C:9]4[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:6][N:7]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=5)[C:8]=4[CH3:13])[CH2:37][CH2:38]3)=[N:29][CH:30]=[CH:31][N:32]=2)=[CH:23][CH:22]=1
Reactant: Cc1c(CC=O)c(CC(C)C)nn1-c1ccccn1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(CCN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c(CC(C)C)nn1-c1ccccn1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
Combine (3-isobutyl-5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-acetaldehyde (0.21 g, 0.82 mmol), 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.21 g, 0.82 mmol) in DCM (10 mL) and stir at room temperature for 15 min. Add glacial acetic acid (0.07 mL, 1.23 mmol) then sodium triacetoxyborohydride (0.26 g, 1.23 mmol). Stir at room temperature for 20 hr. Concentrate, then purify using SCX chromatography and further purify using silica gel chromatography, eluting with 5% 7 M ammonia in methanol:DCM. Dissolve the free base in methanol (5 mL) and treat with ammonium chloride (0.022 g). Concentrate the resulting solution to give the title compound as a white powder (0.22 g, 50%). MS: m/z=500.3 [M+H]+.