Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=2)[C:22]#[N:23])=[CH:16][CH:15]=1.CCN(CC)CC.Cl>CN(C=O)C.O.CCOC(C)=O.CCOC(C)=O.CCOCC>[N:10]1[C:3]2[C:2]([NH:11][CH2:12][CH2:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][C:19]4[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=4)[C:22]#[N:23])=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1ncnc2scnc12
Reactant: N#Cc1ccnc(Oc2ccc(CCN)cc2)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccnc(Oc2ccc(CCNc3ncnc4scnc34)cc2)c1
Reaction time: 8 h
Yield: 41 %

Procedure:
7-Chlorothiazolo[5,4-d]pyrimidine (0.26 g, 1.5 mmol), 2-[4-(2-aminoethyl)-phenoxy]-isonicotinonitrile (0.36 g, 1.5 mmol) and Et3N (231 mg, 2.3 mmol) were dissolved with magnetic stirring in DMF (10 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. After stirring overnight, the reaction was diluted with H2O (100 mL) and neutralized with 2 N HCl. The mixture was partitioned into a 1:1 solution of EtOAc/Et2O (3×50 mL). The pooled organic fractions were filtered and concentrated in vacuo to afford a yellow gum, 0.54 g. The gum was dissolved in a small volume of EtOAc and passed through a short SiO2 column with EtOAc/Et2O eluent. The appropriate fractions were pooled and concentrated in vacuo to afford 2-{4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]-phenoxy}-isonicotinonitrile (Compound 2; 230 mg) as a white solid: mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.55 (s, 1H), 8.33 (dd, J=5.1, 0.7 Hz, 1H), 7.39-7.29 (m, 2H), 7.20 (dd, J=5.1, 1.3 Hz, 1H), 7.17-7.13 (m, 1H), 7.13-7.06 (m, 2H), 6.27 (s, 1H), 3.95 (dd, J=12.6, 6.2 Hz, 2H), 3.05 (t, J=7.1 Hz, 2H); ESIMS m/z 375.2 ([M+H]+).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.COC(OC)OC.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Yield: 99.3 %

Procedure:
0.182 g (1.00 mmol) of biphenyl-4-carbaldehyde and 0.224 g (1.20 mmol) tert-butyl piperazine-1-carboxylate were dissolved in 10 mL dry DCM. 0.35 mL (3.0 mmol) of trimethylorthoformate and 0.21 mL (1.50 mmol) triethylamine were then added to the reaction mixture at room temperature for 1 hr. The reaction was quenched with a solution of NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous solution extracted with EtOAc 2×. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo to give 0.35 g (100%) of 51 which was used as is for the next reaction.
Reaction SMILES: [Cl-:1].[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[CH2:7][CH:8]([OH:14])[CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11].CS(C)=O.[O:20]=[C:21]1[NH:29][CH:28]=[N:27][C:26]2[N:25]([CH2:30][CH2:31][C:32](OC3C=CC([N+]([O-])=O)=CC=3)=[O:33])[CH:24]=[N:23][C:22]1=2.CO>CC(C)=O>[Cl-:1].[O:20]=[C:21]1[NH:29][CH:28]=[N:27][C:26]2[N:25]([CH2:30][CH2:31][C:32]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[CH2:7][CH:8]([OH:14])[CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11])=[O:33])[CH:24]=[N:23][C:22]1=2
Reactant: C[N+](C)(C)CC(O)CC(=O)NCCN
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CO
Solvent: CS(C)=O
Product: C[N+](C)(C)CC(O)CC(=O)NCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 1 h
Yield: 33 %

Procedure:
248 mg (1.0344 mmol) of 4-[(2-aminoethyl)amino]-2-hydroxy-4-oxo-N,N,N-trimethyl-1-butanaminium chloride was placed into a 10 ml round bottom flask with magnetic stirring bar. Then 2 ml of dimethylsulfoxide was added and the solution was gently heated to help dissolve the amine. 340 mg (1.034 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was added to the stirring solution. The solution was stirred for a period of one hour and 3 ml of methanol was added. Then 3 ml of acetone was added and the solution was filtered. The solid was washed several times with acetone and allowed to dry. This yielded 105 mg of 4-[[2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]ethyl]amino]-2-hydroxy-4-oxo-N,N,N-trimethyl-1-butanaminium chloride (AIT-0090) as a white solid. m.p. approximately 260-265 (dec) Yield: 33%.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([SH:17])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>C(O)C>[CH2:22]([S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Sc1nnc(-c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCSc1nnc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-phenylphthalazine-1-thiol (Example 1B) (238 mg, 1 mmol) in ethanol (40 ml) is added aqueous KOH (1 molar, 1 ml). After 10 minutes, allylbromide (0.1 ml, 1 mmol) is added, and the mixture is stirred at room temperature for 4 days. After the solvent is evaporated, the residue is extracted with CH2Cl2. The organic phase is evaporated and the residue is stirred with isopropyl ether. Filtration gives the pure title compound, which is recrystallized from ethanol (130 mg). (R1=vinyl, R2=phenyl, A=benzene, Y1=CH2, m=0, n=1, p=0, q=0).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14](=O)(O)[O-].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
1.9 g of 2-chloro-4-hydroxybenzoic acid was dissolved in 20 ml dimethylformamide, and 1.8 g of methyl iodide and 1.2 g of potassium bicarbonate were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 1.7 g of methyl 2-chloro-4-hydroxybenzoate was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][O:20]C(C3C=CC=CC=3)[O:18][CH2:17]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH2:17][OH:18])[CH2:21][OH:20])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(OC3COC(c4ccccc4)OC3)nc2)cc1
Agent: Cl
Solvent: CO
Product: OCC(CO)Oc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Benzyloxy-2-(2-phenyl-[1,3]dioxan-5-yloxy)pyridine was mixed with 20 ml of 4N hydrochloric acid and 20 ml of methanol and stirred at RT for 2 h. The methanol was concentrated in vacuo and the resulting acidic solution was made alkaline with saturated sodium carbonate solution. The alkaline solution was extracted with ethyl acetate, and the organic phase was concentrated.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C-]#N.[K+].[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CO>[CH3:1][N:2]([CH3:3])[C:18]1([C:5]#[N:6])[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reaction time: 65 h

Procedure:
200 ml methanol, 1,680 ml aqueous dimethylamine solution (40 wt. %), 303 g dimethylamine hydrochloride and 200 g potassium cyanide were added to 200 g 1,4-dioxa-spiro[4.5]decan-8-one and the mixture was stirred for approx. 65 hours. The white suspension obtained was extracted four times with 800 ml ether each time, the combined extracts were concentrated, the residue was taken up in approx. 500 ml methylene chloride and the phases were separated. The methylene chloride phase was dried over sodium sulfate, filtered and concentrated. 265 g 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile were obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49]S(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:56]O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:56])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COCCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 65.2 %

Procedure:
To an ice cooled solution of 0.240 g (0.319 mmol) of crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 10(a)] in 3 ml of absolute methanol was added 0.0 17 g (0.383, 1.2 equiv.) of sodium hydride (55% suspension in mineral oil). The reaction was then stirred for 6 h at 50° C., allowed to cool to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 2:1 v/v mixture of hexane and ethyl acetate as eluent to yield 0.143 g (0.208 mmol, 65.2% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 689 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:18][OH:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:25]([OH:27])([CH3:26])[O:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2=NOC(C)(O)C2c2ccccc2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A dry, 250 mL 3-neck round-bottom flask, equipped with a thermometer, magnetic stirring bar, reflux condenser and rubber septum was charged with 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one oxime (from Example 2, Step 2) (2.50 g, 9.64 mmol) and anhydrous THF (100 mL) under a nitrogen blanket. The solution was cooled to -20° C., and n-butyllithium (1.6N, 15.0 mL) was added, via syringe, over 20 minutes, keeping the reaction temperature <-10° C. The deep red suspension was stirred at -20° C. for 1 hour, warmed to room temperature, and stirred at room temperature for 1 hour. Acetic anhydride (1.1 mL, 11.6 mmol) was added in one portion, and the yellow reaction was stirred for 2 hours without temperature control. The reaction was poured into aqueous hydrochloric acid (1N, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic solution was washed once each with aqueous hydrochloric acid (1N, 100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude oil. The oil was applied to a column of silica gel (250 ml) and eluted with ethyl acetate/hexane (10-40% ethyl acetate) to yield, upon concentration of the appropriate fractions, 986 mg of 3-(3-fluoro-4-methoxyphenyl)-4-hydrido-5-hydroxy-4-phenyl-5-methylisoxazole. This intermediate was dissolved in tetrahydrofuran (40 mL). Sulfuric acid (conc., 0.9 mL) was added, and the reaction was warmed to reflux. After one hour, the solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2×50 mL). The combined organic solution was washed with aqueous hydrochloric acid (1N, 50 mL), saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude, dark oil. Washing the oil with 50% dichloromethane in hexane dissolved the compound but did not dissolve the dark impurities. The resulting solution was evaporated under reduced pressure to yield 797 mg (29%) of 3-(3-fluoro-4-methoxyphenyl)-5-methyl-4-phenylisoxazole as a foam. Mass Spectrum: MH+=284. Anal. Calc'd. for C17H14NO2F: C, 72.07; H, 4.98; N, 4.94. Found: C, 72.13; H, 4.98; N, 4.92.
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=CC=1)CCC.C[N:33](C=O)C.S(Cl)(Cl)=O>C1COCC1>[CH2:25]([N:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:31][C:19]=2[CH:20]=[C:21]([C:28]([NH2:33])=[O:29])[CH2:22][CH2:23]1)[CH2:26][CH3:27]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (16 ml) was added dropwise to a solution of 4-[3-(imidazol-1-yl)propyl]aniline (0.42 g) and triethylamine (2.1 ml) in THF (12.6 ml) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[imidazol-1-yl]propyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 287) (0.80 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.CC1(C)COB(C2C(F)=C(C=CC=2)C#N)OC1.CC1(C)COB(C2C(C#N)=C(F)C=CC=2)OC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[N:13]3)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Agent: CC1(C)COB(c2cccc(C#N)c2F)OC1
Agent: CC1(C)COB(c2cccc(F)c2C#N)OC1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1

Procedure:
In the attempted coupling of trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) with a 1:1 mixture of 3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-fluorobenzonitrile and 6-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-fluorobenzonitrile (34.4 mg) following the procedure described in Example 35 part c), none of the expected product was obtained. Instead, the triflate was reduced, affording 5-(4-fluorophenyl)-2-trifluoromethyl[1,8]naphthyridine (13.9 mg, 42%). δH (360 MHz, CDCl3) 7.27-7.31 (2H, m), 7.46-7.50 (2H, m), 7.55 (1H, d, J 4.6), 7.82 (1H, d, J 8.4), 8.49 (1H, d, J 8.8), 9.27 (1H, d, J 4.6). m/z (ES+) 293 [MH]+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:39]5[CH2:40][CH2:41][C@@H:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:38]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CS(C)=O
Product: Cn1cc(-c2cc3c(-c4cccc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 95 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
A mixture of 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (50.0 mg, 0.13 mmol) and (R)-3-(Boc-amino)pyrrolidine (246.1 mg, 1.32 mmol) in DMSO (2.6 mL) in a sealed tube was stirred at 95° C. under N2 for 3 days. The cooled reaction mixture was diluted into 1:1 ether-ethyl acetate. The organic layer was washed with 10% aqueous citric acid until pH ˜4 to 5, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate) to give tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate as a foam (61.4 mg, 85.3%). 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.79 (s, 1H), 8.05 (broad s, 1H), 7.97 (s, 1H), 7.62-7.50 (m, 2H), 6.37 (d, J=7.9 Hz, 1H), 5.86 (dd, J=8.5, 2.2 Hz, 1H), 4.79 (s, 1H), 4.44 (s, 1H), 4.07-3.95 (m, 4H), 3.92-3.84 (m, 1H), 3.84-3.69 (m, 3H), 3.63-3.51 (m, 1H), 2.64-2.49 (m, 1H), 2.37 (td, J=13.6, 7.7 Hz, 1H), 2.17 (d, J=9.8 Hz, 2H), 2.11-2.01 (m, 1H), 1.89-1.68 (m, 3H), 1.46 (s, 9H). LC/MS: m/z 545.3 [M+1].
Reaction SMILES: C([Li:5])CCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N12CCN(CC1)CC2.ClC1C(OCOC)=C(C(C2C=CC=CC=2OCOC)=C)C=CC=1>CCCCCC.O1CCCC1.CCOCC>[C:6]1([S:12][CH2:13][Li:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: CSc1ccccc1
Agent: C1CN2CCN1CC2
Agent: C=C(c1ccccc1OCOC)c1cccc(Cl)c1OCOC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]CSc1ccccc1
Temperature: 0 °C

Procedure:
Phenylthiomethyl lithium was prepared by adding 120 ml of 2.5M butyl lithium in hexane to a solution of 37.3 g of thioanisole and 33.7 g of 1,4-diazabicyclo[2,2,2]octane in 400 ml of tetrahydrofuran dropwise with stirring at 0° C. and then allowing the mixture to react for 45 min at 0° C. and 1 hour at room temperature. A solution of 50.2 g of 1-(3-chloro-2-methoxymethoxyphenyl)-1-(2-methoxymethoxyphenyl)ethene dissolved in 100 ml of tetrahydrofuran was added slowly to this at ambient temperature with stirring. A brick red color developed. The mixture was heated to reflux for about 30 min. Analysis by gas-liquid chromatography indicated that the reaction was complete. The mixture was cooled, diluted with ether, and quenched with water. The solution was extracted several times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 80 ml of a pale orange oil. This was subjected to a bulb-to-bulb distillation at up to 120° C. and 0.3 mm of mercury pressure. The thioanisole impurity was removed and a product cut of less than 5 ml was collected. Considerable decomposition took place. The product cut was partially purified by liquid chromatography, eluting with a 95:5 mixture of hexane and ether to obtain 1.8 g of the title compound of about 82 percent purity (gas-liquid chromatography) as a viscous oil. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C[O:12][C:13](=O)[CH:14]([CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=O)[CH3:16].C(O)(=O)C>CO>[CH2:21]([O:20][CH2:19][CH2:18][C:14]1[C:13]([OH:12])=[N:9][CH:8]=[N:10][C:15]=1[CH3:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=CN
Reactant: COC(=O)C(CCOCc1ccccc1)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ncnc(O)c1CCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
NaOMe (2.75 g, 50 mmol) is added to a stirred solution of formamidine acetate (25 mmol) in MeOH (75 ml) at room temperature. The mixture is stirred for 15 minutes. 2-(2-Benzyloxy-ethyl)-3-oxo-butyric acid methyl ester (20 mmol) is added and the mixture is stirred at room temperature overnight. Acetic acid (1.5 g, 20 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and the mixture is extracted with 2-butanone (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid (160).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[OH:14])[CH:2]=[CH2:3]>ClCCl.CC#N.CC#N.Cl[Pd]Cl>[CH:1](/[C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[OH:14])=[CH:2]\[CH3:3]
Reactant: C=CCc1ccc2ncccc2c1O
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: C/C=C/c1ccc2ncccc2c1O

Procedure:
Treatment of 6-allylquinolin-5-ol in dichloromethane with bis(acetonitrile)dichloropalladium (II) following the procedure described for Example 3c affords 6-[(1E)-prop-1-enyl]quinolin-5-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2=[O:32])[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OC)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)S(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 22) (187 mg, 0.5 mmol) in CH2Cl2 (20 mL) was added 3-chloroperoxybenzoic acid (77%, 112 mg, 0.5 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. CH2Cl2 (100 mL) was added and the mixture washed with saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 1:1) gave (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-8-one (Compound No. 24) as separate diastereomers. (Diastereomer 1, white foam, 44 mg; Diastereomer 2, white solid, 290 mg).