Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([Sn:11]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])O)[CH2:8][CH2:9][CH3:10].O>C1(C)C(C)=CC=CC=1>[C:1]([O:6][Sn:11]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCCC[Sn](O)(CCCC)CCCC
Solvent: Cc1ccccc1C
Solvent: O
Product: C=C(C)C(=O)O[Sn](CCCC)(CCCC)CCCC
Yield: 64 %

Procedure:
Methacrylic acid (0.1 mol) and tri-n-butylhydroxystannane (0.1 mol) were dissolved in xylene and subjected to reaction. The water that formed as the reaction proceeded was removed together with the solvent by distillation. The by-product of the reaction was distilled off under vacuum and the residue was dried under vacuum to obtain tri-n-butylstannyl methacrylate (m.p. 46° C.; yield, 64%). This tri-n-butylstannyl methacrylate was put into a round-bottom flask and xylene was added to attain a concentration of ca. 50%. As a polymerization initiator, benzoyl peroxide (1 mol % of)the tri-n-butylstannyl methacrylate) dissolved in xylene was charged into a dropping funnel. After equipping the flask with this funnel, the benzoyl peroxide solution was dripped in an amount of about 10% of the total quantity. Thereafter, the flask was heated to the reflux temperature and the remaining initiator was slowly added dropwise until the reaction was completed in 8 hours. After the reaction, the content of the flask was added to n-hexane and subjected to re-precipitation. The resulting precipitate was recovered and dried to obtain poly(tri-n-butylstannyl methacrylate). Yield, 80%, Mn, 30,000; Mw/Mn=1.8, IR (ν -1), 1700, 1160, 700; atomic absorption spectrum (Sn content), 31.44 (found) and 31.64 (calculated).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[C:29]1[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:31][CH:30]=1>CCCCCCC.C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:34]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)n1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and ethyl 6-bromo-2-pyridinecarboxylate (commercially available) using a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow foam (89%). MS (Turbo Spray): m/z=540.2 [M+H].
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[CH:11]=[C:12]([CH:45]=[C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:47]=1[OH:48])[C:13]([O:15][CH2:16][CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([NH:28][C:29](=[O:44])[CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=2)=[O:32])[CH:22]=1)=[O:19])=[O:14])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[CH2:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([C:31](=[O:32])[CH:30]([Cl:4])[C:29]([NH:28][C:23]2[CH:22]=[C:21]([O:20][C:18]([CH2:17][CH2:16][O:15][C:13](=[O:14])[C:12]3[CH:11]=[C:10]([C:6]([CH3:7])([CH3:8])[CH3:9])[C:47]([OH:48])=[C:46]([C:49]([CH3:51])([CH3:50])[CH3:52])[CH:45]=3)=[O:19])[CH:26]=[CH:25][C:24]=2[Cl:27])=[O:44])=[CH:38][CH:37]=1)[CH2:41][CH2:42][CH3:43]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCOc1ccc(C(=O)CC(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)C(Cl)C(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 99 %

Procedure:
Sulphuryl chloride (4.9 g, 36.2 mmole) in dichloromethane (10 ml) was slowly added to a solution of the 4 equivalent coupler from (f) (24.1 g, 36.2 mmole) in dichloromethane (140 ml). After stirring at room temperature for 21 hours, the volatiles were removed by rotary evaporation. The product was isolated as a yellow oil (25.1 g, 99%) and was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C/C=C(/C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of (2Z)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]acrylonitrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were removed in vacuo and the product was stirred with THF (1.5 mL), sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) for 2 hours. The reaction mixture was neutralized by the dropwise addition of conc. HCl. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (16 mg, 76%).
Reaction SMILES: OC(C(F)(F)F)=O.C([O:15][CH2:16][CH:17]1[CH2:20][CH:19]([C:21]2[CH:32]=[CH:31][C:24]([CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:22]=2)[CH2:18]1)C1C=CC=CC=1.CC(O)C>C(O)C.[Pd]>[N:26]1([CH2:25][C:24]2[CH:31]=[CH:32][C:21]([CH:19]3[CH2:18][CH:17]([CH2:16][OH:15])[CH2:20]3)=[CH:22][CH:23]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: c1ccc(COCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Yield: 79 %

Procedure:
To a stirring solution of crude 1-[4-(3-benzyloxymethyl-cyclobutyl)-benzyl]-pyrrolidine TFA salt prepared above (61.5 mmol) in 250 mL of ethyl alcohol was added palladium black (4.0 g, 20% by wt). The Parr bottle was then pressurized with H2 to 45 psi. After complete consumption of starting material as evident by LRMS the reaction vessel was evacuated (removal of H2 gas), then the reaction was filtered through a plug of Celite, and concentrated under reduced pressure. The residual was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3. The aqueous layer was back extracted with 3:1 CHCl3:iPrOH. The organic layers were dried over magnesium sulfate, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography, using a Biotage column 75 large, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.2% NH4OH, through 20% MeOH/CH2Cl2 w/0.2% NH4OH. The product containing fractions were collected and concentrated, 13C NMR revealed the presence of TFA. The product was free based by reaction with aqueous K2CO3, and extracted with 3:1 CHCl3:iPrOH to yield the title compound (11.9 g, 79% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][CH:29]([CH3:32])[CH2:30][NH2:31]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([NH:31][CH2:30][CH:29]([CH3:32])[CH3:28])=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CC(C)CN
Product: CC(C)CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-methylpropan-1-amine via General Procedure B. The product was purified via reverse phase HPLC to give 13.2 mg of 256. MS (Q1) 436.8 (M)+.
Reaction SMILES: C[C:2]1([OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:11])[CH:3]1[CH3:12].CC1C2C(=CC=CC=2)C(C)=C1C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:12][CH:3]1[CH:4]([CH3:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:13]
Reactant: CC1c2ccccc2C(C)(O)C1C
Agent: CC1=C(C)C(C)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1C(=O)c2ccccc2C1C
Temperature: 25 °C
Yield: 45.1 %

Procedure:
In a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus and a reflux condenser 2,3-dimethyl-1-indanone (34) (19.2 g, 0.12 mol) was dissolved in dry diethyl ether (300 ml) under an argon atmosphere. Methyllithium (46.3 ml, 3 M solution in diethoxymethane, 0.14 mol) was added dropwise via a syringe and the mixture was refluxed overnight. The mixture was cooled to 0° C. and a solution of saturated ammonium chloride (100 ml) was added dropwise through the top of the condenser. The mixture was transferred into a separation funnel, the organic layer was washed with water (3×100 ml), dried over magnesium sulfate and filtered. The ether was removed under reduced pressure to afford the raw 1,2,3-trimethyl-1-indanol (19.34 g, 92%) as a yellow liquid which was used for the next step without further purification. Toluene (300 ml) was added to the raw 1,2,3-trimethyl-1-indanol (19.34 g, 0.11 mol) and the solution was transferred into a 500 ml round bottomed flask fitted with a Dean-Stark trap and a magnetic stirring apparatus. p-Toluene sulfonic acid (50 mg, 0.26 mmol) was added and the solution refluxed overnight. After completion of the removal of the water the excess toluene was removed via distillation through the Dean-Stark arm, the residue was cooled to ambient temperature, diluted with diethyl ether (100 ml), washed with a saturated solution of sodium bicarbonate (3×100 ml), dried over magnesium sulfate and filtered. After removal of the solvent in vacuo, the liquid was purified via column-chromatography [(SiO2, 50×9 cm) eluent: cyclohexane:ethylacetate (10:1)] to afford two fractions: 1,2,3-Trimethylindene (37) (8.92 g, 51%) as a pale yellow liquid Rf 0.41; (34) (7.94 g, 45%) (starting material) was obtained as a dark yellow liquid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1)=[O:3].O.O.Cl[Sn]Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>Cl.CCOCC>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of 39.8 g of 4-chloro-3-nitroacetophenone and 136 g of SnCl2.2H2O in 220 ml of concentrated HCl is stirred at room temperature for 0.5 hours. The reaction mixture warms spontaneously to 70° C. then cools. Toluene (200 ml) is added and the reaction mixture is made alkaline with 30% NaOH. Ether is added and the layers are separated. The aqueous layer is extracted twice more with ether, the organic layers are combined, dried, and evaporated. The solid residue is crystallized from benzene to yield 29.6 g of the title compound, melting point 104°-105° C.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([C:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[N:10][C:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCC>[N:9]([C:20]1([NH:26][C:27]([NH:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[N:10][C:11]1([NH:17][C:18]([NH:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1(N=NC2(N=C=O)CCCCC2)CCCCC1
Reactant: NNc1ccccc1
Solvent: CCCCC
Product: O=C(NNc1ccccc1)NC1(N=NC2(NC(=O)NNc3ccccc3)CCCCC2)CCCCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4.52 grams (.041 moles) of phenylhydrazine in 25 ml of pentane in a 125 ml erlenmeyer flask cooled in an ice bath was slowly added a solution of 5.77 grams (.0205 moles) of 1,1'-azobis (1-isocyanatocyclohexane) (from Example XCI) in 25 ml of pentane. After the addition was complete, the reaction was stirred an additional 90 minutes at 0° to 5° C. and filtered. The filter cake was washed with cold pentane and air dried. The dry white powder weighed 5.7 grams (57% crude yield) and melted at 148°-151° C. with decomposition. The infrared spectrum of the product contained a strong broad carbonyl band at 1670-1700 cm-1 and NH peaks at 3200-3340 cm-1. The isocyanate band of the starting material at 2225 cm-1 was absent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]C(C)(C)C.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>CCOCC>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: BrCCCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(CCCc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a solution of 3.8 mL (25 mmol) of 1-bromo-3-phenyl propane in 200 mL of ether at −78° C. was slowly added 30 mL (50 mmol) of t-BuLi (1.7 M in pentane). The reaction mixture was warmed to −20° C. for 15 min, then it was recooled to −78° C. To this reaction mixture was slowly added a solution of 2.61 g (13.8 mmol) of 1-benzyl-4-piperidone in 20 mL of ether. After 15 min, the reaction mixture was poured into, 200 mL of sat'd NH4Cl solution. The reaction mixture was extracted with ethyl acetate and the combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4 filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 1:1) to give 3.3 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[N:3]1.CC1C=C([N+]([O-])=O)C=C2C=1C=NN2.[H-].[Na+].CI>CN(C)C=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[N:3]1
Reactant: Cc1cc([N+](=O)[O-])cc2c1cnn2C
Agent: Cc1cc([N+](=O)[O-])cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(N)cc2c1cnn2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
1,4-Dimethyl-6-nitro-1H-indazole. 4-Methyl-6-nitro-1H-indazole (0.75 g, 4.23 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (0.203 g, 5.08 mmol, 60% dispersion in mineral oil) was then added at ambient temperature. After 15 minutes, methyl iodide (0.318 mL, 5.08 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to the solution and allowed to stir at ambient temperature. After 2 h, LCMS analysis showed two peaks in the UV trace, both with the same product masses as geometric isomers. The solution was condensed under reduced pressure to give a brown solid. The solid was diluted with water (25 mL) and sonicated for 5 minutes. The resultant solid was filtered and washed with additional water followed by hexanes to afford a tan solid. The solid was purified via column chromatography (Biotage, eluting with 0-100% ethyl acetate in hexanes) to afford the title compound (0.480 g, 2.51 mmol, 59% yield) as verified via 1H NMR and NOE NMR. NOE-NMR (400 MHz, DMSO-d6) δ (ppm) 4.18 (Irradiate peak). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 (s, 1H), 8.35 (s, 1H), 7.77 (s, 1H), 4.18 (s, 3H), 2.66 (s, 3H); MS (ESI) m/z 192.4 [M+1]+.
Reaction SMILES: NC1N=CN=C2N(CC3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)N=C(I)C=12.[F:30][C:31]1[CH:32]=[C:33]([C:39]2[C:47]3[C:42](=[N:43][CH:44]=[N:45][C:46]=3[NH2:48])[NH:41][N:40]=2)[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1.Br[CH:50]([C:52]1[O:53][C:54](=[O:80])[C:55]2[C:60]([C:61]=1[C:62]1[CH2:68][CH:67]3[N:69]([C:70]([O:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=4)=[O:71])[CH:64]([CH2:65][CH2:66]3)[CH:63]=1)=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH3:51]>>[NH2:48][C:46]1[N:45]=[CH:44][N:43]=[C:42]2[N:41]([CH:50]([C:52]3[O:53][C:54](=[O:80])[C:55]4[C:60]([C:61]=3[C:62]3[CH2:63][CH:64]5[N:69]([C:70]([O:72][CH2:73][C:74]6[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=6)=[O:71])[CH:67]([CH2:66][CH2:65]5)[CH:68]=3)=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH3:51])[N:40]=[C:39]([C:33]3[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=[C:31]([F:30])[CH:32]=3)[C:47]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1C1=CC2CCC(C1)N2C(=O)OCc1ccccc1
Agent: Nc1ncnc2c1c(I)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3C3=CC4CCC(C3)N4C(=O)OCc3ccccc3)c3ncnc(N)c23)c1
Yield: 92.1 %

Procedure:
Title compound was prepared following the procedure described for the synthesis of Intermediate D1, from 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 52.4 mg, 0.202 mmol) and benzyl 3-(3-(1-bromoethyl)-1-oxo-1H-isochromen-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (Intermediate C40, 100 mg, 0.202 mmol) to give Benzyl 3-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (125 mg, 0.186 mmol, 92% yield) as a yellow solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH:9]([C:18](OC(C)(C)C)=O)[C@H:10]([C:15]([OH:17])=O)[C:11]([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:18][NH:9][C@@H:10]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:15]([N:9]([CH3:18])[CH3:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: CN(C)C(=O)[C@@H](NCc1cccc(C(C)(C)C)c1O)C(C)(C)C

Procedure:
The title compound is prepared according to the representative synthesis of aminophenol 2g except for the following changes: 1) Initial amide formation carried out with Boc-Tle-OH instead of Boc-Val-OH. 2) The product from the reduction process is quenched with a saturated solution of aqueous NaHCO3 (formation of the HCl salt is omitted) and the desired product is purified by silica gel chromatography (9:1 hexanes:ethyl acetate to 6:1 hexanes:ethyl acetate to 4:1 hexanes:ethyl acetate) to afford 2h as a white solid. M.p.=96-98° C. IR (neat): 2948 (w, br), 1639 (s), 1460 (m), 1433 (m), 1352 (m), 1240 (m), 1135 (m), 878 (m), 782 (m), 751 (s) cm−1; 1H NMR (400 MHz, CDCl3): δ 10.87 (1H, br s), 7.19 (1H, d, J=7.3 Hz), 6.77 (1H, d, J=7.3 Hz), 6.70 (1H, t, J=7.5), 4.09 and 3.40 (2H, ABq, JAB=13.6 Hz), 3.31 (1H, d, J=11.3 Hz), 3.03 (3H, s), 2.89 (3H, s), 2.71 (1H, br s), 1.40 (9H, s), 0.96 (9H, s); 13C NMR (100 MHz, CDCl3): δ 173.3, 157.0, 137.2, 126.9, 126.3, 122.9, 118.5, 62.4, 51.3, 38.0, 35.8, 34.8, 34.7, 29.6, 27.0; HRMS Calcd for C19H33N2O2 [M+H]+: 321.25420. Found: 321.25442. [α]20D=−33 (c=0.93, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:15])=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[C:13]([CH3:15])[CH3:12])[C:8]#[N:9])=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: COc1ccc(CC#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C#N)=C(C)C)cc1

Procedure:
According to the procedure described by Example 1, p-methoxybenzylcyanide (18.6 g, 127 mmol) is condensed with acetone (50 ml) under addition of methanol (6.5 ml) and KOH (3.33 g, 50 mmol) to yield, after workup and distillation at 111-113° C./0.05 mbar, 2-(4-methoxyphenyl)-3-methyl-but-2-ene nitrile (14.3 g, 18%).
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.NC(C)(C)C([NH:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[C:40](=[O:48])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[Cl:47])=O>>[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[C:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[Cl:47])=[O:48]
Reactant: CC(C)(N)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
From 70 g (0.25 mol) of 2-amino-5-nitro-2'-chlorobenzophenone there is obtained, in analogy to the details in paragraph (a) of Example 1, 2-amino-2'-(o-chlorobenzoyl)-2-methyl-4'-nitro-propionanilide of melting point 138°-139° (ether/petroleum ether).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]2[NH:30][N:29]=[N:28][N:26]=2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCCc1ccc(OCCCc2nnn[nH]2)cc1)OCc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A mixture of {4-[4-(3-cyanopropoxy)phenyl]butyl}carbamic acid benzyl ester 2 (0.90 g, 2.5 mmol), sodium azide (0.50 g, 7.5 mmol), and ammonium chloride (0.40 g, 7.5 mmol) in DMF (7 mL), was stirred at 120° C. for 16 h. Inorganics were removed by vacuum filtration. The filtrate was diluted with ethyl acetate, and washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated. The residue was taken up in ethyl acetate (5 mL) and diluted with hexanes (10 mL). Solid precipitates were collected by suction filtration and purified by flash silica gel column chromatography eluting with methanol/dichloromethane (1:50, v/v) to give the desired product 3 as a white solid (0.78 g, 76% yield). 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 4H), 2.20 (m, 2H), 2.50 (m, 2H), 3.10 (m, 4H), 4.00 (m, 2H), 5.00 (s, 2H), 6.75 (d, 2H), 7.05 (d, 2H), 7.30 (m, 5H). m/z (ESI): 410 [C22H27N5O3+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.300 g, 0.763 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.316 g, 0.839 mmol) according to the general procedure VI. Obtained as an off-white solid (0.040 g, 10%). MS (ISP) 532.1 [(M+H)+]; mp 227° C.