Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1[C:22]2[C:13](=[CH:14][C:15]3[C:20]([C:21]=2[C:23](Cl)=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1.[O:26]1CCCC1>>[C:1]([NH:8][C:23]([C:21]1[C:22]2[C:13]([CH:14]=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:24])(=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: NCc1ccccc1
Reactant: C1CCOC1
Product: O=C(NC(=O)c1c2ccccc2cc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 30 ml of benzylamine and 60 ml of tetrahydrofuran is added dropwise with cooling, a solution of 9.86 g of 9-anthroyl chloride in 30 ml of tetrahydrofuran. After stirring at room temperature overnight, the mixture is concentrated, and the residue is dissolved in methylene chloride. The solution is washed with dilute acid and dilute base, dried, and concentrated to give 12.45 g of crude N-benzoyl-9-anthramide. The product is added to a slurry of 2.50 g of sodium hydride (50% in oil, previously washed with hexane) in 80 ml of tetrahydrofuran and the mixture is heated to reflux for 30 min and cooled. Propargyl bromide (6.0 g) in 10 ml of tetrahydrofuran is added, and the reaction mixture is heated under reflux for 2 hours. Water and methylene chloride are added; the layers are separated, and the dried organic layer is concentrated. The residue (crude N-benzyl-N-propargyl-9-anthramide) is heated under reflux with 100 ml of p-xylene for 2.5 hr. On cooling, 9.81 g of 2-benzyl-3,5-dihydro-5,9b-o-benzenobenz [e]isoindol-1-(2H)-one precipitates.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[O:13]([C:15]#[N:16])[K]>O>[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:15]([NH2:16])=[O:13])[CH2:5][CH2:4]1
Reactant: N#CO[K]
Reactant: NC1CCC(=O)c2sccc21
Agent: Cl
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21
Temperature: 70 °C

Procedure:
The aqueous solution (280 ml.) of (+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride from Example 53 is stirred while 40 grams of KOCN in 95 ml. of water is added dropwise. The mixture is warmed to 70° C. for 1.5 hour and cooled to 10° C. The light brown solid is collected and washed well with 700 ml. of water. The product is then stirred with 110 ml. of cold methanol, collected, and washed with 50 ml. of cold methanol to afford 48 grams of the title compound, m.p. 247°-249.5° C. (dec.), [α]D24 = - 97.16° (c, 0.14 in methanol).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCCC2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and pyrrolidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>C(OCC)C>[C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24][NH:33][CH:30]3[CH2:32][CH2:31]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Reactant: NC1CC1
Solvent: CCOCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Reaction time: 22 h

Procedure:
A solution of 4.50 g (11.06 mmol) of ethyl 4-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-α-(ethoxymethylene)-2,5-difluoro-β-oxobenzenepropionate in 50 ml of ethyl ether was treated with 0.77 g (13.5 mmol) of cyclopropylamine and stirred for 22 hours. The title compound was isolated as a syrup after evaporation under vacuum.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1>CC1C=NC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1cccnc1Cl
Solvent: Cc1cccnc1
Product: Clc1cccnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 37.2 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.17 g) and 2,3-dichloropyridine (1.27 g) were dissolved in 3-methylpyridine (6 ml) and stirred under reflux for 16 hours. The majority of the reaction solvent was removed by vacuum distillation (120 torr, 70°-80° C.) and the residue was neutralised with aqueous potassium carbonate (5%; 40 ml), washed with water (2×100 ml) and extracted into chloroform (40 ml). The chloroform extract was evaporated under reduced pressure and subjected to column chromatography (chloroform:methanol 25:1) to give the title compound as an oil (1.15 g). This was treated with oxalic acid as in Example 1 to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-3-chloropyridine dioxalate (1.1 g), m.p. 154°-5° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](Cl)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[C:16]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)(=[O:18])[CH3:17]
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a cold (10° C.) mixture of 44.0 g (0.212 mol) of 2-bromonaphthalene and 34.0 g (0.255 mol) of aluminum chloride in 400 ml of nitrobenzene was added 21.0 g (267 mmol) of acetyl chloride. The mechanically stirred reaction mixture was warmed to room temperature, and heated to 40° C. for 18 hours. After cooling to 0° C. in an ice bath, the reaction was quenched by the addition of 12M HCl (70 ml). The layers were separated and the organic phase was washed with water and dilute aqueous Na2CO3. Kugelrohr distillation, followed by recrystallization from 10% EtOAc-hexane yielded 23 g of the title compound as a tan solid. 1H NMR (CDCl3): δ 8.44 (1H, br s), 8.04-8.10 (2H, m), 7.85 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.8 Hz), 7.64 (1H, d, J=8.8 Hz), 2.73 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[C:19]([CH2:21][C:22]1([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[C:19]([CH2:21][C:22]1([N:33]2[CH:37]=[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=34)[CH:35]=[N:34]2)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)#[N:20]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.0 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.2 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.2 mmol) and cesium carbonate (3.0 g, 9.2 mmol) in 1,4-dioxane (6 mL) and water (0.9 mL) was degassed and sealed. It was stirred at 90° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-50%) to afford the desired product (1.6 g). LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH:2]=[CH2:3].Cl.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)leucine, prepared as described by F. Guibe, O. Dangles, and G. Balavione in Tetrahedron Letters, 1986, 27, 2365-2368, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)leucine methyl ester
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.75 g, 14.37 mmol) in THF (50 mL) is added tetrabutylammonium fluoride trihydrate (6.8 g, 24.55 mmol) under a nitrogen atmosphere. The reaction mixture is stirred overnight. Water and AcOEt are added, the layers are separated and the aqueous one extracted twice with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 97:3 to 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. MS (LC-MS): 395.1 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.01 min.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH3:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16].ClC([O-])=O>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:16][CH2:15][C:14]([CH3:19])([CH3:13])[CH2:17][OH:18])=[O:3]
Reactant: COc1ccccc1OC(=O)Cl
Reactant: CC(C)(CO)CO
Agent: O=C([O-])Cl
Product: COc1ccccc1OC(=O)OCC(C)(C)CO

Procedure:
The reaction of 2-methoxyphenol chloroformate with 2,2-dimethyl-1,3-propanediol is conducted on a 0.01 mole scale employing the same conditions as described in Example III, except that the addition of the chloroformate solution is accomplished at room temperature. A 1.4 g yield of the pure product is obtained as an oil.
Reaction SMILES: CN.[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][C:14](=O)[CH3:15].[C:17]([BH3-])#[N:18].[Na+].[ClH:21].CN.Cl>CO.CCOCC>[ClH:21].[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][CH:14]([CH3:15])[NH:18][CH3:17]
Reactant: [BH3-]C#N
Reactant: COc1ccc(I)c(CCC(C)=O)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CNC(C)CCc1cc(OC)ccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of 19.41 g (0.625 mole) of methylamine in 400 ml of anhydrous methanol was treated with 37.92 g (0.125 mole) of 4-(2-iodo-5-methoxyphenyl)-2-butanone, 6.28 g (0.1 mole) of sodium cyanoborohydride and 21.07 g (0.312 mole) of methylamine hydrochloride and allowed to stir at room temperature under an atmosphere of nitrogen for 21/2 hours. The resulting mixture was cooled in an ice bath and treated with concentrated hydrochloric acid to pH 1. The solvent was evaporated in vacuo and the residue partitioned between 1.5 l of water and 600 ml of ether. The water layer was separated and treated with 50% sodium hydroxide solution until basic. The resulting crude product was extracted into 500 ml of ether, washed with brine, and the brine layer extracted with an additional 400 ml portion of ether. The combined ether layers were dried over anhydrous potassium carbonate and evaporated in vacuo to yield 31.09 g (78%) of crude oil. The oil was dissolved in methanol and treated with ethereal hydrogen chloride until neutral. Ether was added to the mixture and the resulting hydrochloride salt separated by filtration to give 19.75 g (44%) of crude product. One recrystallization from 2-propanol yielded pure 2-iodo-5-methoxy-N-alphadimethylbenzenepropanamine hydrochloride a white solid, mp 189°-190° C.
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH3:9][C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[C:18]=1[CH:17]=[N:16][NH:15][C:14]2=[O:19]>C1C=CC=CC=1>[CH3:1][N:15]1[C:14](=[O:19])[N:13]2[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:11][C:10]([CH3:9])=[C:18]2[CH:17]=[N:16]1
Reactant: Cc1nc(-c2ccccc2)n2c(=O)[nH]ncc12
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: Cc1nc(-c2ccccc2)n2c(=O)n(C)ncc12
Yield: 100 %

Procedure:
Dimethylformamide dimethyl acetal (0.73 ml; α=0.897, 0.005 mole) is added slowly to a slurry of 8-methyl-6-phenylimidazo[1,5-d]-as-triazin-4(3H)-one (1.13 g, 0.005 mole in benzene (25 ml). The reaction mixture is stirred, refluxed for 24 hours, cooled and filtered. The filtrate is evaporated to yield 1.4 g (100%) product. Recrystallization from methyl cyclohexane yields yellow crystals, found to be identical (ir:nmr) to the product obtained by Method A.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=O)[C:6]([CH3:31])([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[CH3:7])=[O:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:30][C:15]1[CH:16]=[C:17]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=2)[CH:18]=[C:13]([C:10]2[S:9][C:8]([C:6]([C:5]3[O:2][CH:1]=[N:3][N:4]=3)([CH3:31])[CH3:7])=[N:12][CH:11]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)C(=O)NNC=O)s2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)c3nnco3)s2)c1
Yield: 41.7 %

Procedure:
The product from Step 2 (80 mg, 0.172 mmol) was taken up in THF (2 mL) in a microwave vial, and Burgess reagent (82 mg, 0.344 mmol) was added. The reaction was irradiated in the microwave at 100° C. for 30 min. The yellow reaction mixture was concentrated to dryness, and the resulting residue was purified by column chromatography on silica (0-100% ethyl acetate in hexanes) to provide N-(3-methyl-5-{2-[2-(1,3,4-oxadiazol-2-yl)propan-2-yl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (32 mg, 42%) as an off-white solid. MS ESI: [M+H]+ m/z 447.0. 1H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.20 (s; 1H), 8.81 (d, J=4.9, 1H), 7.97 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.14 (s, 1H), 2.29 (s, 3H), 1.87 (s, 6H). rhSYK activity=+++
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:34][C:20]3=[N:21][CH:22]=[CH:23][C:24]([C:25]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=4[O:32][CH3:33])=[C:19]3[CH:18]=2)[CH2:12]1)(C(C)(C)C)(C)C.CO.Cl>ClCCl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:34][C:17]([CH:13]4[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12]4)=[CH:18][C:19]=23)[CH:30]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCO[Si](C)(C)C(C)(C)C)C3)cc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCO)C3)cc12

Procedure:
A solution of Example 128A (80 mg, 0.16 mmol)) in dichloromethane (2 mL) and methanol (2 mL) was treated with 37% hydrochloric acid (0.1 mL) for 10 minutes and concentrated. The residue was purified by reverse phase HPLC, and was eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 370.20 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.56-1.69 (m, 1H) 1.83-2.01 (m, 2H) 2.16 (d, 1H) 2.85-2.99 (m, 1H) 3.14-3.23 (m, 3H) 3.26-3.40 (m, 2H) 3.74 (s, 3H) 3.75-3.80 (m, 2H) 6.11 (d, 1H) 7.09 (d, 1H) 7.18-7.24 (m, 2H) 7.25-7.32 (m, 1H) 8.22 (d, 1H) 9.55 (s, 1H) 11.88 (s, 1H).
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+:17].C(=O)(O)[O-].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:17])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: O=C([O-])O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 177 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
Ammonium picrate (0.18 g, 0.75 mmol) and ammonium bicarbonate (0.59 g, 7.5 mmol) are suspended in sulfolane (3 ml), stirred for 2 hr at 177° C. , cooled to ambient temperature and mixed with water (30 ml). The product is collected, washed with water and dried to yield 0.030 g (16%) of picramide (Table 1, entry 6).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J32) (318 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 73%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Brc1ccccn1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccccn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromopyridine (243 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (346 mg, 68%) as a brown solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([C:11]2[C:19]3[C:18]([N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][C:23](=O)[CH2:24]5)=[N:17][CH:16]=[N:15][C:14]=3[S:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(Cl)Cl>[CH:1]([NH:4][CH:23]1[CH2:22][CH:21]2[N:20]([C:18]3[C:19]4[C:11]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)=[CH:12][S:13][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:25]([CH2:26][CH2:27]2)[CH2:24]1)([CH3:3])[CH3:2]
Reactant: O=C1CC2CCC(C1)N2c1ncnc2scc(-c3ccccc3)c12
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)NC1CC2CCC(C1)N2c1ncnc2scc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropylamine (0.0385 mL, 0.4472 mmol) was added to a solution of 8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (0.05 g, 0.1491 mmol) in DCM (2 mL). Sodium triacetoxyborohydride (0.1663 g, 0.7454 mmol) was added and the mixture was stirred at room temperature overnight. A second batch of isopropylamine (0.0385 mL, 0.4472 mmol) and sodium triacetoxyborohydride (0.1663 g, 0.7454 mmol) was added and the mixture was stirred overnight. A third batch of isopropylamine (0.0385 mL, 0.4472 mmol) and sodium triacetoxyborohydride (0.1663 g, 0.7454 mmol) was added and the mixture was stirred over three nights. Methanol (2 mL) was added to quench the reaction. The solvent was evaporated and the residue was dissolved in dichloromethane (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with dichloromethane (2×2 mL). The combined organic layers were evaporated to give a colourless oil. Mass: 77 mg. This was purified by silica chromatography (10 g cartridge; eluent dichloromethane/0.5 M ammonia in methanol 0 to 10%; all output collected). Fractions containing the target compound (by TLC and LCMS; broad peak) were combined and evaporated to give N-isopropyl-8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-amine a white solid. (19 mg). LCMS RT=3.04 min. M+1=379.