Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]([C:22]#[N:23])[CH3:21])[CH3:17]>C(O)(C)C>[NH2:23][C:22](=[S:8])[CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:24]
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)C#N
Solvent: CC(C)O
Product: CCOC(=O)C(C)C(N)=S
Reaction time: 8 h

Procedure:
A mixture of diphenylphosphinodithioic acid (Alfa-Aesar) (7.48 g, 29.9 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 1.980 mL, 14.94 mmol) in isopropanol (80 mL) was heated under reflux for 8 h then stood at rt overnight. Reaction mixture was filtered and filtrate was diluted with EtOAc and washed with 1N NaOH, brine, and dried over Na2SO4. Crude was purified by chromatography on silica gel using a Hex/EtOAc gradient. Appropriate fractions were combined and evaporated to yield title compound as a yellow oily solid. 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). [ES+MS] m/z 162 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[C:19]([C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)N)([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:19]([C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(ON2C(C)(C)CCCC2(C)C)cc(C(C)(C)C)c1
Yield: 84.4 %

Procedure:
The procedure of Example 1 is repeated using 1.50 g (9.6 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 2.38 g (24 mmol) of tert-butyl nitrite, 5.8 mg (0.0096 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 90 mL of pyridine and 3.93 g (19.2 mmol) of 3,5-di-tert-butylaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 2.8 g of the title compound as an off-white solid in 84.8% yield. The structure is confirmed by 1Hnmr and elemental analysis.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](N1C=CC=CC1=O)([N:12]1C=CC=CC1=O)=[S:11].N.CO>C(Cl)Cl>[NH:1]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:10]([NH2:12])=[S:11]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CNC(N)=S
Reaction time: 18 h

Procedure:
To a magnetically stirred suspension of tert-butyl 2-aminoacetate (11.2 g, 85 mmol) in CH2Cl2 (200 mL) under nitrogen is added 1,1′-thiocarbonyldipyridin-2(1H)-one (21 g, 90 mmol) and the resulting mixture is stirred at room temp. for 18 h. The solvent is removed in vacuo, the residue treated with 2M ammonia in methanol (600 mL, 1200 mmol) and stirred at room temperature for 45 min. The solvent is removed in vacuo and dried under high vacuum to give the title compound as a reddish oil that is used “as is” without further purification in the next step. LC/MS (Condition A): ret. T=2.19 min, (M+H)+ 191—actually see (M−55) 134.95 (this is characteristic of BOC fragmentation pattern).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1.N1C=CC=CC=1.N1(C2C=CN=CC=2)CCCC1.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C(Cl)Cl>[CH3:1][N:2]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1)[C:45](=[O:48])[O:46][CH3:47]
Reactant: COC(=O)Cl
Reactant: CNC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(C)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reaction time: 2 h
Yield: 26.4 %

Procedure:
14 Mar. 2011 To a round bottomed flask was added N-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (0.0999 g, 0.277 mmol), pyridine (0.045 ml, 0.554 mmol), and 4-(pyrrolidin-1-yl)pyridine (0.041 g, 0.277 mmol) to stir at RT in DCM (0.924 ml). Methyl carbonochloridate (0.027 ml, 0.416 mmol) was added and allowed to stir for 2 h. Solvent was evaporated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage 50 g SNAP HP-silica column, eluting with a gradient of 1% to 4% MeOH in CH2Cl2, to provide methyl methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (0.0307 g, 0.073 mmol, 26.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:4][CH:3]=1.O[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[O:9][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: OC(c1ccc(Cl)cc1)c1ccccn1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1

Procedure:
The procedure of Example 32 (a) was repeated except for using (4-chlorophenyl)-2-pyridylmethanol and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-pyridylmethanol and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][Br:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>C(Cl)(Cl)Cl>[Br:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([Cl:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OCCCBr)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
20 ml of a chloroform solution containing 5.8 g of 3-phenoxypropyl bromide was cooled to -10° C., and 3.6 ml of chlorosulfuric acid was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was poured onto ice, and extraction was performed with 100 ml of chloroform. Water washing, drying and concentration were successively carried out to obtain 3.4 g (yield: 40%)of 4-(3-bromopropoxy)benzenesulfonic acid chloride in an oily state.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1N)([O-])=O.[C:16]([CH2:18]C(OCC1C=CC=CC=1)=O)#N.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C>[F:13][C:12]([F:15])([F:14])[O:11][C:9]1[CH:10]=[C:4]2[C:5]([CH:16]=[CH:18][NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: N#CCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 61° C. with gentle stirring, is added 2-nitro-4-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2 h after the addition. The solvent is removed on a rotorvap and the residue is treated with HCl (6 N, 200 mL), and extracted with dichloromethane (3×100 mL). The extracts are combined, dried over anhydrous Na2SO4, and passed through a short silica gel pad. The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2CO3 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45° C. overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3×100 mL). The organics are dried over anhydrous Na2SO4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed with Na2CO3 (2 M, 2×50 mL), water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4-trifluoromethoxyaniline).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: COCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2-(2-methoxyethoxy)ethanol (200 mg, 1.67 mmol, 1 equiv.), triethylamine (232 μL, 1.67 mmol, 1.0 equiv.) and tosyl chloride (317 mg, 1.67 mmol, 1 equiv.) in methylene chloride (5 mL, 0.29 M) was stirred at room temperature for 50 hours. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (10 g, hexanes/EtOAc 9:1 to 1:1) to afford (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate as a colorless oil (260 mg, 457 mg theoretical, 56.9%). LC-MS m/z 275 (M+1).
Reaction SMILES: C1COCC1.C([Li])CCC.[CH3:11][C:12]#[N:13].C([O:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=O)C>O>[O:16]=[C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]#[N:13]
Reactant: CCOC(=O)c1cccs1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)c1cccs1
Temperature: -50 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a flask charged with THF (250 ml) was added dropwise n-butyl lithium (18.4 mL, 46 mmol) at −78° C. under a N2 atmosphere. After addition the resulting solution warmed to −50° C. and dry MeCN (1.86 g, 45 mmol) was added slowly. After 1 h, the reaction was cooled to −78° C. and was treated with thiophene-2-carboxylic acid ethyl ester (6.93 g, 44.5 mmol). After stirring for 1 h the resulting mixture was warmed to RT and stirred for 1 h. Water was added dropwise at 0° C. to quench the reaction and the solution was extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give a solid residue, which was re-crystallized from CH2Cl2. After the solid was collected by filtration, they were redissolved in ethyl acetate (100 mL), and acidified with dilute hydrochloride (2N). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to yield 3-oxo-3-thiophen-2-yl-propionitrile (4.7 g, yield=70%) as a yellow solid, which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:36])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: COc1ccccc1N=C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-methoxyphenyl isocyanate (417 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8i as solid. Yield: 0.623 g, 76.85%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:13]([CH3:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(NC(=O)c2cc(Br)ccc2O)c1
Yield: 58.1 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dimethylaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.CC(C)([O-])C.[K+].[C:17]1(=[O:21])[O:20][CH2:19][CH2:18]1.Cl>O1CCCC1>[C:17]([CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1)([OH:21])=[O:20]
Reactant: O=C1CCO1
Reactant: Cc1cc(O)ccc1C=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OCCC(=O)O)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-hydroxy-2-methylbenzaldehyde (5 g) and potassium tert-butoxide (4.12 g) in tetrahydrofuran (60 mL) was added β-propiolactone (4.6 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate (20 mL)-n-hexane (100 mL). The insoluble material was collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (7.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH:19]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH2:1])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc2[nH]cc(CCN)c2c1)(C(C)C)C(C)C

Procedure:
A solution of 3-(2-amino-ethyl)-1H-indol-5-ol (3.0 g), imidazole (9.6 g), and triisopropylsilyl chloride (4.5 mL) was stirred in 20 mL N,N-dimethylformamide for 6 h. The solution was diluted with 100 mL of ethyl acetate and washed with 100 mL of sodium carbonate and 100 mL of saturated sodium chloride (3 times). The organic phase was dried over sodium sulfate and the solvent was evaporated. Silica gel chromatography (2% methyl alcohol in dichloromethane) gave 2-(5-triisopropylsilanyloxy-1H-indol-3-yl)-ethylamine (2.6 g). This compound was cyclized with formaldehyde by Procedure OO to afford 6-triisopropylsilanyloxy-2,3,4,9-tetrahydro-1H-β-carboline, which was protected with tert-butoxycarbonyl group by Procedure CC to give 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:27])=[CH:16][CH:17]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccc(O)cc3)coc2c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccc(OC)cc3)coc2c1
Yield: 87.6 %

Procedure:
In 150 ml of acetone was dissolved 5.5 g of ethyl {[5-chloro-3-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxy}acetate under heating, and 4.8 g of anhydrous potassium carbonate was added thereto. To the solution was added 3.4 ml of methyl iodide, followed by refluxing for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the insoluble material was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol-chloroform to obtain 5.0 g of the entitled compound having a melting point of 121° to 122° C.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:54])([F:56])[F:55])[CH2:52][N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (8.5 mg, 0.016 mmol) and Intermediate 60 (3.5 mg, 0.013 mmol) to give a white solid (7.6 mg, 74% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.38-7.03 (m, 11H), 7.04-6.82 (m, 3H), 5.12 (t, J=7.3 Hz, 1H), 4.90-4.64 (m, 2H), 4.35 (d, J=14.8 Hz, 1H), 3.98 and 3.82 (2s, 3H), 3.97-3.84 (m, 1H), 3.27 (dd, J=14.8, 6.6 Hz, 6H), 2.95-2.53 (m, 5H), 2.48-2.30 (m, 2H), 2.26-2.14 (m, 1H), 2.04-1.15 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1C=O.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([OH:20])([C:12]([F:14])([F:15])[F:13])[C:16]([F:18])([F:17])[F:19])[CH:8]=[CH:7][C:4]=1[CH:21]=[CH:22][C:23]([OH:25])=[O:24]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=CC(=O)O
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 15 g (0.05 mole) 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzaldehyde in 50 ml of pyridine are added 11 g (0.11 mole) of malonic acid and 1 g of piperidine. The solution is stirred and gradually heated to 80°. Heating and stirring are continued for 1 hour at 80°. The solution is then heated at reflux for an additional 3 hours, cooled, and evaporated at reduced pressure to obtain a residual oil which is extracted into ether. The resulting ether solution is washed with water and 1N hydrochloric acid, dried with anhydrous magnesium sulfate, filtered, and evaporated at reduced pressure to obtain a residual solid which is recrystallized from chlorobutane/hexane mixed solvent to give 10.5 g of 3-{2 -methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-2-propenoic acid having a melting point of 138°-140°.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:40]=1[CH2:41][CH2:42]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:42][CH2:41][C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH2:34])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cnccc1CCO
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cnccc1CCOc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 4-nitronaphthol (2) (0.95 g, 5.00 mmol), PPh3 (1.97 g, 7.50 mmol) and 2-(3-aminopyridin-4-yl)ethanol (25) (1.04 g, 7.50 mmol) in THF (20 mL) was added dropwise DIAD (590 μL, 3.75 mmol) at −15° C. The mixture was stirred for 1 hr at RT and the volatiles removed in vacuo. The residues was absorbed on silica (20 g) and purified by column chromatography (SiO2, 80 g, 50-100% EtOAc in isohexane, gradient elution and then 5% MeOH in EtOAc, isocratic elution) to give the title compound (26) (1.36 g, 88%): m/z 310 (M+H)+ (ES+).
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[C:12]([S:16]([NH2:19])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(S(N)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of Benzenesulfonamide-3-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA41 (9.2 mg, 28% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.0.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[I:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>CCO>[CH2:2]([O:4][C:5](=[O:13])[C:6]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([I:14])=[CH:16][CH:17]=1)([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccc(I)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(I)cc1)C(=O)OCC

Procedure:
220 mg (10 mmol) sodium in small pieces are added to 15 mL EtOH. After 15 min 1.65 mL (9.70 mmol) 2-methyl-malonic acid diethyl ester are added. The mixture is stirred at reflux for 15 min and subsequently 3.00 g (10.1 mmol) 4-iodobenzyl bromide are added. The mixture is stirred at reflux for 12 h. After that time, the solvent is evaporated and the residue is purified by column chromatography (silicia gel; cyclohexane:EtOAc 98:2) to yield the desired product.