Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([CH2:4][NH:5][CH2:6]C2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.CNC.C1COCC1.[BH3-]C#N.[Na+]>>[CH3:4][N:5]([CH3:6])[CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%).
Reaction SMILES: [CH:1]1([N:4]([CH:41]2[CH2:43][CH2:42]2)[C:5]([C:7]2[N:38]([CH2:39][CH3:40])[C:10]3=[N:11][C:12]([N:19](CC4C=CC(OC)=CC=4OC)C(=O)OC(C)(C)C)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:19][C:12]1[N:11]=[C:10]2[N:38]([CH2:39][CH3:40])[C:7]([C:5]([N:4]([CH:41]3[CH2:43][CH2:42]3)[CH:1]3[CH2:3][CH2:2]3)=[O:6])=[CH:8][C:9]2=[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl 7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1I, 2.66 g, 4.51 mmol) in dichloromethane (33.8 mL) was added TFA (11.28 mL). The reaction mixture was stirred at rt 45 min and was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2×) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by flash chromatography using an Isco 40 g column eluting with 4-10% MeOH/CH2Cl2 to yield 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (1.2 g, 3.55 mmol, 79% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2.[O-:17][C:18]#[N:19].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>[Br-].C([N+](CC)(CC)CC)C.C(#N)C>[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:19][C:18]([O:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]([CH3:15])[C@H:6]3[N:5]([CH3:16])[CH2:4][CH2:3][C@@:2]3([CH3:1])[C:9]=2[CH:10]=1)=[O:17]
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Reactant: CCCCCCCBr
Reactant: N#C[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Yield: 63 %

Procedure:
150 g of eseroline (0.69 mole), 83.9 g of potassium cyanate (1.035 moles), 148 g of 1-bromoheptane (0.83 mole) and 29 g of tetraethylammonium bromide (0.14 mole) are placed into 5 l of anhydrous acetonitrile. The reaction mixture is refluxed for 19 hours, the insolubles are filtered off and the mixture is worked up as described in Example 1. Heptastigmine yield is 63%.
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].BrBr.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO>[C:15]1([CH2:14][N:21]2[CH2:2][C:1](=[O:3])[C:4]3([CH2:5][CH2:6]3)[C:7]2=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(C(C)=O)CC1
Reactant: NCc1ccccc1
Agent: BrBr
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of ethyl 1-acetylcyclopropanecarboxylate (7.6482 g, 48.97 mmol) in EtOH (54 mL) was slowly added bromine (2.76 mL, 53.87 mmol) via syringe. The orange solution was stirred for 2 h and then concentrated in vacuo. To a 0° C. solution of the residue in EtOH (54 mL) was added benzylamine (13.4 mL, 122.7 mmol) slowly via syringe, and the mixture was stirred and warmed to room temperature overnight. The mixture was concentrated in vacuo and partitioned between DCM (200 mL) and 1 N aq. HCl (100 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford 5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (2.7842 g, 26%) as a yellow solid. LCMS: (M+H)+: 216.1.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.Br[CH2:19][CH2:20][CH2:21]Br>>[N+:14]([C:10]1[CH:9]=[C:8]([C:7]2([C:6]([OH:5])=[O:17])[CH2:21][CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: BrCCCBr
Product: O=C(O)C1(c2cccc([N+](=O)[O-])c2)CCC1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,3-dibromopropane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclobutanecarboxylic acid.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5]C=[CH:3][CH2:2]1.[CH3:9][Si](Cl)(C)C.[CH3:14][OH:15]>COC(OC)(C)C>[O:15]1[CH:3]2[CH2:2][CH:1]([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH:14]12
Reactant: O=C(O)C1CC=CC1
Reactant: CO
Reactant: C[Si](C)(C)Cl
Solvent: COC(C)(C)OC
Product: COC(=O)C1CC2OC2C1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
3-Cyclopentenecarboxylic acid (J. Org. Chem., 1984, Vol. 49, p. 928) (2.42 g) was dissolved in methanol (8 ml) and 2,2-dimethoxypropane (32 ml), and trimethylsilyl chloride (253 μl) was added dropwise to stir the mixture at room temperature for 6.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane (50 ml), to which m-chloroperbenzoic acid (70%, 4.93 g) was added under ice cooling. After the mixture was heated to room temperature and stirred for 5 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to separate an organic layer. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 2:1) to obtain the title compound (1.59 g) as a colorless oil.
Reaction SMILES: [CH3:1][S:2][CH3:3].[K].ClC1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)C=O>C(OCC)C>[CH3:1][S:2][C:3]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CSC
Reactant: CCOC(=O)c1ccc(Cl)cc1C(=O)OCC
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(SC)cc1C(=O)OCC

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH:26]=[N+]=[N-])[N:17]=[CH:16]2)[C@H:6]1[F:30])(=[O:3])[CH3:2].F[C@@H]1[C@H](O)[C@@H](CO)O[C@@H]1OC.[ClH:42]>ClCCl.C(OCC)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH2:26][Cl:42])[N:17]=[CH:16]2)[C@H:6]1[F:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Reactant: Cl
Agent: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Yield: 75 %

Procedure:
Compound (37) (80 mg) obtained in item (4) above was dissolved in dichloromethane (4 ml), to which was added at 5° C. a 1.25M hydrogen chloride solution (0.2 ml) in diethylether and the mixture obtained was allowed to undergo the reaction at that temperature overnight. The resulting reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate and then concentrated to give the titled compound (38) (61 mg) as a syrup. Yield: 75%.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([CH2:15][CH2:16][NH2:17])=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([CH2:15][CH2:16][NH:17][CH2:20][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1ccc(OCc2ccc(Br)cc2)c(CCN)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CNCCc2nc(C)ccc2OCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A solution of 675 mg (2.10 mmol) of 2-{3-[(4-bromobenzyl)oxy]-6-methyl-2-pyridinyl}ethylamine and 345 mg (2.10 mmol) of methyl 4-formylbenzoate in 5 ml of ethanol is heated at reflux for two hours. The solvent is then removed under reduced pressure and the resulting residue is dissolved in 5 ml of methanol. A total of 159 mg (4.21 mmol) of solid NaBH4 are added a little at a time. After two hours of stirring at room temperature, the mixture is poured into water and extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solution and dried over Na2SO4. After filtration, the solvent is removed under reduced pressure and the resulting crude product is purified by preparative HPLC. This gives 351 mg (0.75 mmol, 35% yield) of a colorless oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C(N([CH2:16][CH3:17])CC)C.[C:18](Cl)(=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:18]([C:2]([C:1]([OH:10])=[O:9])([OH:3])[C:4]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:16][CH3:17])([OH:5])[C:6]([OH:8])=[O:7])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: O=C(O)C(O)C(O)C(=O)O
Product: CCCCCCCCCCCCCCCCCCC(O)(C(=O)O)C(O)(CCCCCCCCCCCCCCCCCC)C(=O)O
Reaction time: 24 h

Procedure:
Into a flask were placed 100 ml dichlomethane, tartaric acid (0.1 mole), triethylamine (0.4 mole), and stearoyl chloride (0.2 mole). The reaction was left for 24 hours with constant stirring. The reaction mixture was washed with 0.1N HCl solution to yield distearyl tartaric acid.
Reaction SMILES: [OH-].[K+].C(O)C.C([O:8][C:9](=[O:32])[C:10]([N:16]([CH3:31])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])([CH3:15])[C:11]([NH:13][CH3:14])=[O:12])C.S([O-])(O)(=O)=O.[K+]>O.C1COCC1>[C:9]([C:10]([N:16]([CH3:31])[C:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18])([CH3:15])[C:11]([NH:13][CH3:14])=[O:12])([OH:32])=[O:8]
Reactant: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(C)(C(=O)O)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 104.6 %

Procedure:
A 0.84 mol/L potassium hydroxide aqueous solution (3.0 mL) was added to an ethanol (3.0 mL)-THF (3.0 mL) solution of 4-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.30 g) as obtained in Example 12-(1), and the mixture was stirred for 4.5 hours at room temperature. Under ice cooling, water and a 2.0 mol/L potassium hydrogen sulfate aqueous solution were added to adjust the mixture to pH 7, followed by extracting the mixture with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered out. The solvent was distilled off under reduced pressure to obtain 4-{[2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}biphenyl (orange solid) (0.29 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4F)[C:18]#[N:19])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C[N:31]1[CH2:35][N:34]=[CH:33][NH:32]1.[C:36]([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:31]4[CH:35]=[N:34][C:33]([CH3:36])=[N:32]4)[C:18]#[N:19])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)n1c(-c2cc(C#N)ccc2F)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: CN1CN=CN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccc(C#N)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 100 °C
Yield: 55.6 %

Procedure:
To a solution of 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-benzonitrile (200 mg, 0.52 mmol) in DMSO (6 mL) are added 2-methyl-1H-1,2,4-triazole (65 mg, 0.78 mmol) and K2CO3 (143 mg, 1.04 mmol) at room temperature. The solution is heated at 100° C. for 12 hours. The solution is cooled down and extracted with EtOAc (2×15 mL) and H2O (20 mL). The combined organic layer is dried with MgSO4 (500 mg) and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent to afford the title compound (130 mg, 56%) as a white solid. LCMS (ESMS): m/z: 450.20 (M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15]CN1C.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([C:28]#[N:29])=[CH:21][N:20]=1.[CH2:30]([N:32](CC)[CH2:33]C)C.C(Cl)Cl.CO.[OH-].[NH4+]>C(O)C>[C:28]([C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][N:32]([CH3:33])[CH2:30]2)=[N:20][CH:21]=1)#[N:29]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: N#Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Cc2c[nH]c3ccc(Nc4ncc(C#N)cc4[N+](=O)[O-])cc23)C1
Yield: 53 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-5-cyano-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 2 hours. Column chromatography using 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide] afforded the title compound (53%) as a red foam: Rf =0.2 in 20% methanol in methylene chloride; 13C NMR (CD3OD) δ 158.3, 140.3, 136.5, 130.0, 128.4, 125.9, 122.2, 120.4, 115.2, 112.8, 111.1, 98.4, 70.1, 57.9, 40.4, 31.3, 28.2, 22.4; HRMS calculated for C20H20N6O2 376.1650, found 376.1653.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(O)(=O)C.[Cl:16]N1C(=O)CCC1=O>O>[Cl:16][C:10]1[CH:9]=[C:6]([O:7][CH3:8])[C:4]([OH:5])=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(C=O)c1O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Cl)cc(C=O)c1O
Temperature: 105 °C
Reaction time: 0.12 h
Yield: 52 %

Procedure:
o-Vanillin (100.5 g, 660 mmol), acetic acid (504 mL) and N-chlorosuccinimide (83.8 g, 627 mmol) were mixed and heated to 105° C. over 30 minutes. A rapid exotherm from 55 to 105° C. occurred over 7 minutes. The mixture refluxed for a few minutes and was allowed to cool slowly to room temperature (2.5 h). Water (1 L, 2 volume equivalents) was added to the mixture slowly over 10 minutes. The mixture was stirred for 5 minutes, filtered and the crude product air dried to afford 146.9 g of wet cake as a light yellow powder with 90% product, 3% o-vanillin and 7% dichlorovanillin Recrystallization from 200 g ethanol afforded 61 g (52% yield).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].C[O:16][B:17]([O:20]C)[O:18]C.Cl>CCCCC.C1COCC1>[C:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:16][B:17]([OH:20])[OH:18])#[N:10]
Reactant: N#Cc1ccccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: N#Cc1ccccc1OB(O)O
Temperature: -76 °C
Reaction time: 0.33 h
Yield: 50.3 %

Procedure:
12.4 ml of a 1.6 M solution of t-butyllithium in n-pentane was dropwise added to 23 ml of THF at −76° C. in about 10 minutes. Then, a solution of 2.0 g (11.0 mmo ) of 2-bromobenzonitrile in 3.0 ml. of THF was dropwise added to the resulting mixture at −76° C. in about 20 minutes, followed by the dropwise addition of 2.3 ml (19.8 mmol) of trimethoxyborane in 7 minutes. The obtained mixture was stirred at −76° C. for 20 minutes, followed by the addition of 13.8 ml of 2N hydrochloric acid. The obtained mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated brine, dried and distilled to remove the solvent. 15 ml of methylene chloride and 15 ml of n-hexane were added to the obtained residue. The obtained mixture was stirred at room temperature for 30 minutes to give a precipitate. The precipitate was recovered by filtration and dried to give 0.9 g of the title compound (yield: 55.7%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[N:34]=[CH:33][N:32](C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)[N:31]=6)[CH:28]=5)[N:23](C5CCCCO5)[N:22]=4)[CH2:15][CH2:14]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[N:34]=[CH:33][NH:32][N:31]=6)[CH:28]=5)[NH:23][N:22]=4)[CH2:17][CH2:18]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc(CN3CCC(CNc4nn(C5CCCCO5)c5ccc(-c6ncn(C(c7ccccc7)(c7ccccc7)c7ccccc7)n6)cc45)CC3)on2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: c1ccc(-c2cc(CN3CCC(CNc4n[nH]c5ccc(-c6nc[nH]n6)cc45)CC3)on2)cc1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
The compound prepared in Example 72 (0.13 g) was suspended in a mixture of tetrahydrofuran (6 mL), methanol (6 mL), water (1.5 mL) and concentrated hydrochloric acid (1.5 mL) and heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into a saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (0.040 g) having the following physical data.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH3:4].[O:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)=[CH:3][N:4]=3)=[N:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cn2)c2nccn12
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: C1COCCO1
Product: N
Product: c1cn2c(-c3cn[nH]c3)cnc(Nc3ccc(N4CCOCC4)cn3)c2n1

Procedure:
In the same way as described for compound 127, step 4 using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(5-morpholin-4-yl-pyridin-2-yl)-amine (100 mg, 0.266 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (77.6 mg, 0.4 mmol), Pd(PPh3)4 (77 mg, 0.066 mmol) and 1.5M Na2CO3 (1.42 mL, 2.13 mmol) in dioxane (4 mL). The crude compound is purified by silica gel column chromatography eluting with 96:4 DCM:NH3 (7M in MeOH) to afford the title compound which is triturated with diethyl ether (12.9 mg, 8%) and converted into the mesylate salt (6.1 mg, 38%) LCMS: Rt 1.95 min (96%), m/z (APCI) 363 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.34 (3H, s, MsOH), 3.20 (4H, m), 3.83 (4H, m), 7.38 (1H, br s), 7.64 (1H, br s), 7.71 (1H, s), 7.86 (1H, d), 7.98 (1H, d), 8.04 (2H, m), 8.35 (2H, br s), 8.43 (1H, s).