Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.CN(CCN(C)C)C.[CH2:20]([N:22]([CH2:35][CH3:36])[C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:24])[CH3:21].C(=O)=O.CC(C)=O.[Cl:44][CH2:45][Si:46](Cl)([CH3:48])[CH3:47]>C1COCC1.CCOCC>[CH2:35]([N:22]([CH2:20][CH3:21])[C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[Si:46]([CH2:45][Cl:44])([CH3:48])[CH3:47])=[O:24])[CH3:36]
Reactant: CCN(CC)C(=O)c1cccc2ccccc12
Reactant: C[Si](C)(Cl)CCl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c([Si](C)(C)CCl)ccc2ccccc12
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (20.3 mL, 26.4 mmol) was added dropwise to an ether/liquid nitrogen-cooled solution of TMEDA (4.0 mL, 26.5 mmol) in THF (15 mL), maintaining the internal reaction temperature <-80° C. To this mixture was added a solution of N,N-diethyl-1-naphthalenecarboxamide (5.0 g, 22.0 mmol) in THF (10 mL), again maintaining the internal reaction temperature <-80° C. The resulting solution was stirred with dry ice/acetone cooling for 30 min, then was recooled to <-80° C. with an ether/liquid nitrogen bath while chloromethyl dimethylsilyl chloride (3.8 mL, 28.8 mmol) was added dropwise. The mixture was warmed to RT to afford a green solution which was diluted with ether and extracted with dilute aq citric acid (2 X), followed with sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and chromatographed with 3:17 ethyl acetate/hexanes to afford 4.3 g of N,N-diethyl-2-[(chloromethyl)dimethylsilyl]-1-naphthalenecarboxamide as a yellow oil, a 59% yield.
Reaction SMILES: [H-].[Na+].O1CCCC1.C(OCC)(=O)[CH2:9][C:10]([CH3:12])=[O:11].F[C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C(O)(=O)C>[F:24][C:23]1[C:18]([CH2:9][C:10](=[O:11])[CH3:12])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=[CH:21][C:22]=1[F:25]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 1 h
Yield: 90 %

Procedure:
12.1 g (303 mmol) of 60% sodium hydride was added to 45 ml of tetrahydrofuran, and while cooling with a freezing mixture, 90 ml of tetrahydrofuran containing 39.0 g (300 mmol) of ethyl acetoacetate was dropped to the solution below 20° C. through 30 minutes. After the solution was stirred for 1 hour as was, 90 ml of tetrahydrofuran solution containing 26.6 g (150 mmol) of 2,3,4-trifluoronitrobenzene was dropped to the solution below 10° C. through 30 minutes, and the solution was stirred overnight at room temperature. 27 ml of acetic acid was added to the solution, and the solvent was removed by distillation. The solution was extracted with 500 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. 30 ml of 4N hydrochloric acid and 25 ml of acetic acid were added to the solution, and the solution was heated at reflux for 24 hours. 550 ml of concentrated hydrochloric acid and 550 ml of acetic acid were added to the solution, and the solution was heated at reflux for 16 hours. After air-cooling, the solution was extracted with 1 l of chloroform and was washed with 500 ml of water two times. The solution was further washed with 300 ml of aqueous saturated sodium hydrogen carbonate solution two times, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 300 g, eluent solvent; chloroform: n-hexane=1 :3) to obtain 31.2 g of the subject compound (148) in a 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([NH:34][S:35]([CH2:38]Cl)(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][S:35]([CH2:38][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22])(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)NS(=O)(=O)CCl
Product: CC(C)(C)NS(=O)(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-tert-Butyl-1-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and N-tert-butyl-1-chloromethanesulfonamide following General Procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:27])[CH3:12])[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cn[nH]c2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cn[nH]c2c1-c1cccc(F)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
A mixture of 1-[4-chloro-7-(3-fluorophenyl)-1H-indazol-6-yl]ethanone (2.365 g, 8.192 mmol), ammonium acetate (6.31 g, 81.9 mmol) and sodium cyanoborohydride (1.03 g, 16.4 mmol) in methanol (30 mL) and acetonitrile (30 mL) was heated at 65° C. overnight, in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the crude product (2.37 g). LCMS calculated for C15H11ClFN2 (M−NH2)+: m/z=273.1; Found: 273.0.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[CH:18]=2)(O)[CH3:15])[CH:10]=[CH:11][C:12]=1[Cl:13]>CO>[Br:6][C:7]1[CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[CH:18]=2)=[CH2:15])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COc1ccc(C(C)(O)c2ccc(Cl)c(Br)c2)cc1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: C=C(c1ccc(OC)c(C)c1)c1ccc(Cl)c(Br)c1

Procedure:
Concentrated sulfuric acid (1.5 mL) was added cautiously to a stirred solution of 1-(3-bromo-4-chlorophenyl)-1-(4-methoxy-3-methylphenyl)-ethanol (6.7 g, 0.019 mol) in methanol (200 mL). The reaction mixture was stirred at reflux for 90 minutes then concentrated to remove methanol. The residue was partitioned between hexane (100 mL) and water (150 mL) and the layers separated. The aqueous fraction was extracted with hexane (2×75 mL) and the combined organic extracts were washed with brine (75 mL), dried (sodium sulfate) and concentrated to give the crude product as a yellow oil, which was purified by dry flash chromatography (0 to 1% ethyl acetate/hexane) to give the alkene as a slowly crystallising colourless oil (4.5 g, 70%), mp 79-81° C. 1H NMR (300 MHz; CDCl3) 7.61 (1H, d, J 2.1, Ar), 7.39 (1H, d J 8.3, Ar), 7.21 (1H, dd J 8.3 & 2.1, Ar), 7.09-7.06 (2H, m, Ar), 6.79 (1H, d, J 8.3, Ar), 5.41 (1H, s, olefinic), 5.33 (1H, s, olefinic), 3.85 (3H, s, OMe), 2.21 (3H, s, Me).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C(=O)C)=[CH:6][C:5]=1[OH:14].OS(C(F)(F)F)(=O)=O.[C:24](Cl)(=[O:26])[CH3:25].CCOC(C)=O>O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:24](=[O:26])[CH3:25])[C:7]([OH:10])=[CH:6][C:5]=1[OH:14]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)c(O)cc1O
Temperature: 25 °C

Procedure:
The toluene solution from Step 1 was cooled in an ice bath under N2 and triflic acid (9.44 L) added slowly over 3 h. On stirring a fine white solid was formed which dissolved on warming to RT over 20 h and then stirring at RT for 37 h to give a yellow solution. To the solution was added acetyl chloride (726 mL) and the solution stirred at RT for a further 1 h. This solution was cannulated into a stirred cooled (0° C.) solution of EtOAc (217.8 L) and NaOAc.3H2O (14.52 Kg) dissolved in water (145 L). The organic phase was washed with saturated brine (twice, 72.6 L), and was evaporated to 5.5 Kg. Toluene:Isopropanol (2:3) was added and the crystalline solid removed by filtration and dried to give 12.6 Kg (61% over 2 steps), mp 124-126° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7].[BH4-].C1COCC1.CO.[C:22]([O:26][C:27](ON=C(C1C=CC=CC=1)C#N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][C:27](=[O:28])[O:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [BH4-]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A 3-methylamino-4-nitrobenzonitrile (2.91 g, 16.4 mmol, Journal of Medicinal Chemistry (2001), 44(17), 2753-2771) was treated with borohydride-THF solution (1M THF solution, 65.6 ml) and the mixture was stirred for 3 hours at 0° C. After the addition of MeOH, the mixture was partitioned with water and EtOAc. The crude product was extracted with EtOAc and the organic layer was washed with water and dried over MgSO4. Then, filtration, evaporation gave the yellow colored oil, which was used for the next reaction without purification. The residue was dissolved in 1,4-dioxane (10 ml), and then 2[{(tert-butoxycarbonyl)oxy}imino]-2-phenylacetonitrile (3.13 g, 12.7 mmol) was added. After stirring for 14 hours at room temperature, the residue was concentrated in vacuo followed by the purification through silica gel column chromatography eluting with hexane/EtOAc (20:1) to give tert-butyl [(3-methylamino-4-nitrophenyl)methyl]carbamate as yellow colored solid (864 mg, 19%). 1H NMR (CDCl3): δ 1.47 (9H, s), 3.02 (3H, d, J=5.3 Hz), 4.31 (2H, d, J=5.9 Hz), 4.96 (1H, s), 6.56 (1H, d, J=9.3 Hz), 6.73 (1H, s), 8.08 (1H, brs), 8.14 (1H, d, J=8.6 Hz). MS (ESI) m/z 282 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:5]2.[NH2:36][NH2:37]>O1CCOCC1>[NH:36]([C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:5]2)[NH2:37]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nc4cc3-c3ccccc3)cc2)CCC1
Reactant: NN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(NN)nc4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C

Procedure:
To a microwave vial was added tert-butyl {1-[4-(6-chloro-3-phenyl-1,5-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) (4.05 g, 8.34 mmol), anhydrous hydrazine (5.24 mL, 167 mmol), and 1,4-dioxane (15 mL). The reaction mixture was then heated under microwave irradiation for 5 minutes at 100° C. (high absorption). The reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl {1-[4-(6-hydrazino-3-phenyl-1,5-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) as an orange solid/foam. MS (M+H)+: observed=482.3, calculated=482.59.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:11]1C=CC=C2[C:12]=1[CH2:13][CH2:14]C2=O)(O)=[O:9].Cl.CNC>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:8](=[O:9])[CH2:11][CH2:12][C:13]#[CH:14]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: CNC
Agent: Cl
Product: C#CCCC(=O)Nc1ccccn1

Procedure:
The desired product was prepared by substituting 4-pentynoic acid and 2-aminopyridine for 4-carboxy-1-indanone and dimethylamine hydrochloride, respectively, in Example 40. MS (APCI(+)) m/e 175.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][CH:26]([CH2:28][C:29](O)=O)[CH3:27].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O=P(Cl)(Cl)Cl>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:29]([CH2:28][CH:26]([CH3:27])[CH3:25])=[N:14][N:13]=3)[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=1
Reactant: CC(C)CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(CC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
In a 150 mL RBF was weighed 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.16 g, 2.55 mmol) followed by THF (20 mL), isovalerianic acid (0.29 mL, 2.55 mmol) (TCI America) and N-ethyl-N-isopropylpropan-2-amine (1.11 mL, 6.37 mmol). To this stirring suspension was added HATU (1.07 g, 2.80 mmol) in one portion and the solution was stirred at RT for 2 h. The mixture was concentrated and treated with POCl3 (10 mL, 107 mmol) under argon. The flask was fitted with a reflux condenser and the reaction was heated to 110° C. for 14 h. The excess POCl3 was removed under reduced pressure and the crude residue was treated with EtOAc and a saturated solution of NaHCO3. It was extracted with EtOAc (50 mL) and washed with brine and dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (0-50% EtOAc in Hex) affording 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-isobutyl-1,3,4-oxadiazole (277 mg, 35%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 522.0 (M+H)1. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1H), 8.17 (d, J=8.6 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.97 (m, J=8.2 Hz, 2H), 7.87 (s, 1H), 7.43 (m, J=8.2 Hz, 2H), 2.84 (d, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.15 (dt, J=13.5, 6.8 Hz, 1H), 0.99 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]>C(O)CCC.O>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[O:18][CH2:1][CH2:2][CH2:3][CH3:11])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Solvent: CCCCO
Solvent: O
Product: CCCCOC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(SC)cc1

Procedure:
This compound was prepared following the general procedure E, using 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-hydroxypropyl]phenoxy]-2-methylpropanoic acid in 50/50 butanol/water at 70° C. for 32 hours;
Reaction SMILES: B(F)(F)F.[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8](N)[CH:7]=1.N(OC(C)(C)C)=O.[I-:24].[K+].II>C1COCC1.CCOCC>[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8]([I:24])[CH:7]=1
Reactant: [I-]
Reactant: Nc1cc(Br)c2sc(N)nc2c1
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: II
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc2cc(I)cc(Br)c2s1
Temperature: -2.5 °C
Reaction time: 0.67 h
Yield: 64.9 %

Procedure:
To THF (6 L) at −78° C. under N2 atmosphere was added BF3-etherate (50% assay, 708 mL, 2.81 mol) followed by slow addition of a solution of 7-bromobenzothiazole-2,5-diamine (275 g, 1.02 mol) in THF (500 mL) over 20 min. Tert-butyl nitrite (548 L, 4.61 mol) was then added to the solution at −78° C. The reaction mixture was stirred at the same temperature for 40 min then warmed to −5-0° C. Et2O was added (at −5-0° C.) and stirring continued at the same temperature for 20 min. The precipitated solid was filtered then taken in acetone at 0° C. followed by sequential addition of potassium iodide (510 g, 3.07 mol) and iodine (519 g, 2.04 mol) and stirred at 0° C. for 30 min. After the completion of reaction the mixture was quenched with a saturated solution of sodium metabisulfite then extracted with EtOAc (3×5 L). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at 45° C. The residue thus obtained was purified over basic alumina (30-35% EtOAc-hexane) to obtain the desired product (235 g, 65%) as a light brown solid. 1H NMR (DMSO-d6): δ 7.50 (d, J=1.20 Hz, 1H), 7.63 (d, J=1.20 Hz, 1H) and 7.91 (br s, 2H). LCMS: 354.90 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:57]1[N:62]=[C:61]2[N:63]([CH2:75][CH3:76])[C:64]([C:66]([N:68]([CH:72]3[CH2:74][CH2:73]3)[CH:69]3[CH2:71][CH2:70]3)=[O:67])=[CH:65][C:60]2=[C:59]2[N:77]([CH3:80])[CH:78]=[N:79][C:58]=12>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:72]1([N:68]([CH:69]2[CH2:70][CH2:71]2)[C:66]([C:64]2[N:63]([CH2:75][CH3:76])[C:61]3=[N:62][C:57]([NH:7][C:4]4[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=4)=[C:58]4[N:79]=[CH:78][N:77]([CH3:80])[C:59]4=[C:60]3[CH:65]=2)=[O:67])[CH2:74][CH2:73]1
Reactant: Cn1ccc(N)n1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Br)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ccn(C)n3)nc21
Temperature: 80 °C
Yield: 29.4 %

Procedure:
To a vial containing 1-methyl-1H-pyrazol-3-amine (11.89 mg, 0.122 mmol), Pd2(dba)3 (4.67 mg, 5.10 mmol), Xantphos (5.90 mg, 10.20 mmol), and cesium carbonate (100 mg, 0.306 mmol) was added 4-bromo-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 97A, 41.0 mg, 0.102 mmol) in DME (1020 μL). The reaction mixture was sparged with argon for 5 min, the vial was capped, and the reaction mixture was heated at 60° C. for 4 h and 80° C. for 16 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by flash column chromatography using an Isco 40 g column eluting with 0-5% MeOH/CH2Cl2 followed by additional purification with preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(1-methyl-1H-pyrazol-3-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (13 mg, 0.030 mmol, 29.5% yield) was isolated as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]/[CH:15]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=1.CN(C)[CH:44]=[O:45].Cl>C(OCC)C.O1CCCC1>[Si:25]([O:24][CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:14]=[CH:13]/[C:9]1[N:8]=[C:7]([CH:44]=[O:45])[CH:12]=[CH:11][CH:10]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC(/C=C/c1cccc(C=O)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
1.16 ml of n-butyllithium (1.6 molar in hexane) is instilled in a suspension of 500 mg of 2-bromo-6-[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine in 2 ml of diethyl ether and 1 ml of tetrahydrofuran at -80° C. under argon atmosphere. After completion of the addition, the reaction mixture is stirred for 15 minutes at -40° C., cooled to -80° C. and mixed by instillation at this temperature with 140 mg of dimethylformamide. After 4 hours at -80° C., the reaction mixture is hydrolyzed with 3 ml of 2 n hydrochloric acid, the organic phase is separated, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-10% ethyl acetate. 385 mg of 6-[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine-2-carbaldehyde is obtained as yellow oil.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[N:6]=1.O.C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:11][C:7]1[N:6]=[C:5]([C:2]#[N:3])[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(Br)n1
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(C#N)n1
Temperature: 165 °C
Reaction time: 15 h

Procedure:
Copper(I) cyanide (2.68 g) was added to 2-bromo-6-methoxypyridine (5.62 g) in N,N-dimethylformamide (112 mL) at room temperature, followed by stirring at 165° C. for 15 hours. The resultant mixture was cooled in air. Water and ethyl acetate was added to the mixture. The insoluble matter that was formed in the mixture was filtered by Celite. The filtrate was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid substance (1.78 g, 44%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]3)[NH:13][CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]3)[N:13]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([CH3:24])=[CH:22][CH:21]=3)[CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(CC1)NC2
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2CC3)cc1

Procedure:
Reaction of Intermediate 26 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.[OH-].[Na+]>CN(C=O)C>[Si:11]([O:10][CH2:9][C:7]1[N:8]=[C:3]([CH2:2][NH2:1])[CH:4]=[CH:5][CH:6]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: NCc1cccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6-aminomethypyridine-2-methanol (5 g, 36.2 mmol) in anhydrous DMF (25 mL) at 0° C. was treated with tert-butyldimethylsilyl chloride (5.728 g, 38 mmol) and imidazole (2.584 g, 38 mmol), stirred at room temperature for 20 h, poured into 1.5-M aqueous NaOH (100 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with water (4×10 mL), brine (2×20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil; NMR δH (400 MHz, CDCl3) 0.82 (9H, s), 0.87 (6H, s), 1.81 (2H, s), 3.84 (2H, s), 4.73 (2H, s), 7.03 (1H, d, J 8.0 Hz), 7.28 (1H, d, J 7.5 Hz) and 7.57 (1H, t, J 8.0 Hz); M/Z 253 (M+H)+