Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O-:11].[Na+].O>CO.C(COC)OC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][O:11][CH3:10])[CH:3]=1
Reactant: C[O-]
Reactant: BrCc1cccc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: COCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 3-bromobenzyl bromide (15.0 g, 60 mmol) in methanol-dimethoxyethane (DME) (30 ml+10 ml), sodium methylate (4.9 g, 90 mmol) was added under cooling with ice. The mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water and extracted with ether. The organic layer was washed by an aqueous saturated solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to obtain the title compound ( 12.1 g) having the following physical data.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]#[N:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:4][C:2]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]#[N:18])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: N#CCc1ccccc1N
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccccc1CC#N
Temperature: 155 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
p-Toluenesulfonic acid (2 mg, 0.16 mmol) and acetonylacetone (2.14 g, 18.7 mmol) were added sequentially to a solution of 2-aminophenylacetonitrile (2.06 g, 15.6 mmol) in toluene (30 mL). The reaction mixture was heated in an oil bath at 155° C. for 1 hour and then allowed to stand at ambient temperature overnight. Acetonylacetone (0.5 mL) and a small amount of p-toluenesulfonic acid were added and the reaction mixture was heated at reflux for 4 hours. The toluene layer was washed sequentially with saturated sodium bicarbonate and water (×2), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to a dark oil. The oil was purified by prep HPLC (AnaLogix, eluted with a gradient of 10-30% ethyl acetate in hexanes) to provide 3.35 g of 2-(2,5-dimethylpyrrol-1-yl)phenylacetonitrile as a pale brown oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25]C(=O)C(F)(F)F)[CH:23]=2)[CH:18]=[CH:17]1)[C:8]([O:10][CH3:11])=[O:9].O1CCCC1.[ClH:37]>CO>[ClH:37].[NH2:25][C:22]1[CH:23]=[C:24]2[C:19]([CH2:18][CH:17]=[C:16]2[CH2:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH3:3])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(CC2C=Cc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2=CCc3ccc(N)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Sodium borohydride (0.24 g), was added to a 0° C. mixture of methyl 3-methoxy-4-[6-(trifluoroacetamido)-1H-inden-1-ylmethyl]benzoate (1.25 g), tetrahydrofuran (14 ml) and methanol (2 ml). After 15 min, the reaction was stirred at room temperature for 2 h and cooled to 0° C. 1N Hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed (sodium bicarbonate, water, brine) and dried (MgSO4). Evaporation, dissolution in ether (50 ml) and addition of ethereal hydrogen chloride (5 ml) afforded methyl 4-(6-amino-3H-inden-1-ylmethyl)-3-methyoxybenzoate hydrochloride (0.85 g, 79%) as a colorless solid; mp 213.0°-215.0° C.; MS(CI), m/e=310 (M+H).
Reaction SMILES: [I:1]I.[CH2:3]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([NH:10][C:11]1[C:16]([I:1])=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc(NCc2ccccc2)nc(N)n1
Reactant: II
Solvent: CO
Product: Cc1nc(N)nc(NCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
Iodine (3.04 g, 12.0 mmol) was added to a solution of N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 10.9 mmol) in anhydrous MeOH (50 mL) at 0° C. The reaction was allowed to warm to room temperature overnight. After 12 hours, an additional 0.5 equiv of iodine was added, and the reaction warmed to 50° C. After four hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with 10% NaHSO3 (200 mL). The aqueous phase was separated and washed once more with ethyl acetate (200 mL). The organic phases were combined, washed with brine, separated and dried over Na2SO4, The filtrate was concentrated in vacuo to afford the product N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 85% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:4]=2[O:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(N(CCCC)CCCC)CCC>CN(C)C1C=CN=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:6]2[C:5]3[CH:9]=[CH:10][C:11]([N:13]([S:18]([CH3:21])(=[O:19])=[O:20])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:4]=3[O:3][C:2]([CH3:22])([CH3:1])[C:7]2=[O:8])=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2NC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Temperature: 20 °C
Reaction time: 26 h
Yield: 95.4 %

Procedure:
N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide (7.50 g), 4-fluorophenylboronic acid (5.27 g), 4-dimethylaminopyridine (0.53 g), tributylamine (3.20 g) and copper(II) acetate monohydrate (0.43 g) were added to dimethylsulfoxide (56 mL), and the mixture was stirred at 20° C. for 26 hours under blowing air (7 to 10 mL/min) thereto. The reaction mixture was added dropwise to a mixed solution of dimethylsulfoxide/concentrated hydrochloric acid/water (19 mL/4.5 g/34 mL) at about 15° C., and washed with dimethylsulfoxide (7.5 mL). The mixture was stirred at 10° C. for 3 hours, then the precipitated crystals were successively washed with dimethylsulfoxide/water (12 mL/3 mL) and water (75 mL), and then dried to obtain the title compound (9.09 g) as white crystals (yield: 95%, purity: 92%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C@@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[NH:13][CH2:12]1)=[O:10].O>N1C=CC=CC=1>[CH:1]1([C:4]([N:13]2[C@H:14]3[C@@H:24]([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:26]=4[C:16]([CH2:15]3)=[CH:17][NH:18]5)[CH2:25][C@@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)C2CC2)C1
Reaction time: 1 h

Procedure:
There were slowly added 6 ml of cyclopropanecarboxylic acid chloride to an iced solution of 15 g of 8β-methoxycarbonylergoline in 170 ml of pyridine. The reaction mixture was left at room temperature for 1 hr, then poured into cooled acid water. The precipitate was filtered and crystallized from methanol to give 16 g of 6-cyclopropanoyl-8β-methoxycarbonylergoline melting at 276°-278° C.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.Br[CH2:23][C:24]1[O:25][C:26](=[O:30])[O:27][C:28]=1[CH3:29]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:23][C:24]1[O:25][C:26](=[O:30])[O:27][C:28]=1[CH3:29])=[O:19]
Reactant: Cc1oc(=O)oc1CBr
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: Cc1oc(=O)oc1COC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21
Yield: 27 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 660 mg) and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (639 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-16, 188 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4C3CCCCO3)=[CH:11][CH:10]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.Cl.CCOC(C)=O.O>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:13][CH:14]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2cnn3C2CCCCO2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ncc23)cc1
Yield: 73.8 %

Procedure:
4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1-(tetrahydro-pyran-2-yl)-1H-indazole (0.4 g, 0.888 mmol) and 1N HCl (1.8 mL, 1.8 mmol) in 10 mL MeOH were heated to reflux for 5 hrs. The reaction was cooled and distributed between EtOAc and H2O. The water layer was made basic to pH 12 and the organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 20-100% ethyl acetate in hexanes to yield 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole as a white solid (240 mg, 73.7%). LC-MS (ES) calculated for C21H16F2N2O2, 366.37; found m/z 367 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(CBr)c1
Reaction time: 48 h

Procedure:
A solution of 12 g of m-bromomethylbenzoic acid 10.62 g of oxalyl chloride, 100 ml of dichloromethane and 5 drops of dimethylformamide was allowed to stand 48 hours and then evaporated. Hexane and ether were added, the mixture evaporated and the residue distilled on a Kugelroher, giving 12.5 g of m-bromomethylbenzoyl chloride as a yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:8]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1)#[N:2].CO.O.O[Li].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([OH:27])=[O:26])[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)[C:8]=1[O:9][CH2:10][CH:11]1[CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(C#N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(C#N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a stirred solution of ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.125 g, 0.272 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (34 mg, 0.816 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography to afford 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (50 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.70 (m, 4H), 7.61 (s, 1H), 7.51 (s, 1H), 3.71 (t, 1H), 3.55 (m, 2H), 2.00 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 1.02 (m, 1H), 0.91 (d, 6H), 0.45 (m, 2H), 0.05 (m, 2H).
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.[Na+].[I-]>[CH2:20]([N:19]([CH3:18])[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Reactant: CNCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(=O)C(C)N(C)Cc1ccccc1
Yield: 33.4 %

Procedure:
A mixture of 2.37 g (13.4 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, 1.74 ml (13.4 mmol) of N-methyl benzylamine and 50 mg of NaI in 15 ml of MeOH was refluxed overnight. The mixture obtained after evaporation of the solvent was purified on an Al2O3 column, and recrystallized from ether/hexane to obtain 1.5 g of 2-(benzyl(methyl)amino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1041.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:45][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCc1ccc(OCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCc1ccc(OCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
The compound (67.0 mg) obtained in Example 79-3 was dissolved in anhydrous methanol (1.5 ml) and then added with sodium cyanoborohydride (20.0 mg), acetic acid (1.50 ml), and 2-imidazole carboxaldehyde (23.0 mg), followed by stirring under a nitrogen atmosphere at 60° C. for 2 days. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:32][O:33][C:34]=1[CH3:35]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[C:31]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[N:32][O:33][C:34]=5[CH3:35])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2ccccc2)c1CBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1onc(-c2ccccc2)c1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-(bromomethyl)-5-methyl-3-phenylisoxazole, to give the desired product as a brown oil (71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].C(N(C(C)C)CC)(C)C.[C:22]([O:25][CH2:26][C:27](Cl)=O)(=[O:24])[CH3:23]>ClCCl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c(COC(C)=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 2,3-diamino-benzoic acid methyl ester (40.8 mmol) and diisopropylethyl amine (8.5 mL, 49.0 mmol) in dichloromethane (80 mL) at −30° C. was added dropwise a solution of acetoxy acetyl chloride (4.8 mL, 44.9 mmol) in DCM (15 mL). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with satd. ammonium chloride (50 mL), the layers separated and the aqueous phase extracted with DCM (60 mL). The combined organic layers were washed with brine and dried (MgSO4). The residue after concentration was dissolved in acetic acid (50 mL) and heated at 100° C. for 30 min. The solution was concentrated and purified by flash chromatography (eluent DCM-ethyl acetate 3:1, 2:1, 1:1) to give 2-acetoxymethyl-1H-benzoimidazole-4-carboxylic acid methyl ester (7.3 g, 72% yield over 2 steps) as an off-white solid.
Reaction SMILES: BrC1C=C(C[N:11]([CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)=[O:13])C=CC=1OC.[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].[C:55](=[O:58])([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:12][C:14]4[CH:15]=[C:16]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([CH:44]=[O:45])[CH:47]=5)[C:17]([O:58][CH3:55])=[CH:18][CH:19]=4)=[O:21])[CH:15]=3)=[O:13])[C:25]([NH:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(OC)c(Br)c1)C(=O)c1cccc(C(N)=O)c1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1

Procedure:
N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.64 g, 0.99 mmol), (3-formylphenyl)boronic acid (0.193 g, 1.29 mmol), potassium carbonate (0.41 g, 2.97 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol) were combined in dioxane (6 mL) and water (2 mL). The mixture was microwaved at 150° C. for 30 min. The reaction mixture was diluted with EtOAc and washed 3× with H2O. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to give the title compound as a white solid. LC-MS m/z 675.1 (M+H)+, 1.85 min (ret time); mp 118-121° C.; analytical HPLC shows 100% purity, (ret time 13.204 min).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:5]1([CH2:4][CH2:3][CH2:2][N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][N:21]=3)[CH2:18][CH2:19]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(c1)nnn2CCCN1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
1-(3-chloropropyl)-1H-benzotriazole (11.7 g, 0.06 mol) was dissolved into 150 ml of acetonitrile, 3-(piperidine-4-yl)benzisoxazole (10.1 g, 0.05 mol), diisopropylethylamine (25.8 g, 0.02 mol) and potassium iodide (8.3 g, 0.05 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 12.6 g compound (I-84) with a yield of 69.7%. ESI-MS [M+H]+: m/z 362.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)(=O)C.[BH3-]C#N.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:36]
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (0.2 g, mmol) in dichloroethane (3 mL) was added morpholine (5 equiv.) in 5 mL MeOH and acetic acid (2 equiv.) and the mixture was stirred at room temperature for 15 minutes. Then NaBH3CN (1.5 equiv.) was added and the reaction stirred at room temperature for 16 hours. After completion (monitored by TLC), aqueous sodium bicarbonate was added to the reaction mixture till pH 7-8, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate: hexane to afford the title compound as an off-white solid. LCMS: 574.25 (M+1)+; HPLC: 97.17% (@254 nm) (Rt; 3.906; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B: 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B): 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (a, 1H), 8.20 (t, 1H), 8.01 (d, 1H, H=7.2 Hz), 7.50 (d, 1H, J=7.6 Hz), 7.46 (s, 1H), 7.27 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.83 (m, 2H), 3.59-3.61 (m, 6H), 3.22-3.30 (m, 2H), 3.08-3.10 (m, 2H), 3.03 (m, 1H), 2.43 (s, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).