Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+].C(C(N)CBr)(O[C:23](C)([CH3:25])[CH3:24])=O>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:23]([CH3:25])[CH3:24])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)(C)OC(=O)C(N)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of compound 3 (5.000 g, 17 mmol) in DMF (15 mL) was added K2CO3 (3.51 g, 26 mmol) and Boc-2-amino ethyl bromide (4.56 g, 20.35 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4 and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (4.08 g, 55%) as white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([S:32][CH2:33][CH2:34][C:35](Cl)=[O:36])=[O:31])=[CH:28][CH:27]=1>O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[N:15]([C:35](=[O:36])[CH2:34][CH2:33][S:32][C:30](=[O:31])[C:29]2[CH:38]=[CH:39][C:26]([CH3:25])=[CH:27][CH:28]=2)[C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(C(=O)SCCC(=O)Cl)cc1
Reactant: CC(=O)Oc1ccccc1C1N[C@H](C(=O)O)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1ccccc1C1SC[C@@H](C(=O)O)N1C(=O)CCSC(=O)c1ccc(C)cc1
Reaction time: 1 h

Procedure:
2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 2.6 g of S-(4-methylbenzoyl)-3-mercaptopropanoyl chloride is added dropwise with stirring under icecooling. After the addition, the mixture is stirred under icecooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.6 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.7 g (57%), mp. 93°-96° C. (benzene). [α]D24 +80.4° (c=1.0, methanol).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH:21]([CH3:40])[O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>C1COCC1>[C:36]([Si:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:22][CH:21]([CH3:40])[CH2:20][N:14]1[CH2:15][CH2:16][N:11]2[N:10]=[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=[C:12]2[C:13]1=[O:17])([CH3:38])([CH3:39])[CH3:37]
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Reactant: CC(CBr)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN1CCn2nc(COc3ccccc3)cc2C1=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
2-Phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 0.25 mmol) was added to a suspension of (rac)-(2-bromo-1-methyl-ethoxy)-tert-butyl-diphenyl-silane (0.23 g, 0.62 mmol) and 60% dispersion of sodium hydride in mineral oils (11 mg, 0.29 mmol) in THF (2 mL) at 0° C. The mixture was allowed to reach room temperature and stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[NH2:14][C:15]1[C:16]([Cl:27])=[N:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:27][C:16]1[C:15]([NH:14][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:12])=[CH:20][CH:19]=[C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]=1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)n1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2cn(C)c3ccccc23)c(Cl)n1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
Oxalyl chloride (1.10 ml, 12.5 mmol) was added to a solution of 1-methylindole-3-carboxylic acid (2.00 g, 11.4 mmol) and DMF (0.18 ml, 2.28 mmol) in methylene chloride (25 ml) and the resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent to give 1-methylindole-3-carboxylic acid chloride (2.19 g, 99%) as a pale yellow solid. The resulting 1-methylindole-3-carboxylic acid chloride (752 mg, 3.88 mmol) was added in portions to a solution of ethyl 3-amino-2-chloro-6-pyridylacetate (833 mg, 3.88 mmol) and triethylamine (1.08 ml, 7.77 mmol) in methylene chloride (20 ml) under stirring at 0° C. The reaction mixture was heated under reflux for 8 hours. After cooling to room temperature and addition of water, the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (2:1, v/v) eluate fractions, ethyl 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetate (859 mg, 60%) was obtained as a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[BrH:30]>>[Br:30][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:7]=1
Reactant: Br
Reactant: OCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: BrCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
the alcohol (20) (0.200 gm., 0.65 mmol) was dissolved in 5 mL HBr (45%) and refluxed for 6 hours. After cooling to room temperature the mixture was poured over 20 gm. of crushed ice, basified with saturated aqueous solution of Na2CO3 and extracted with CH2Cl2. The extracts were dried over (MgSO4) and evaporated to dryness to yield the bromo derivative (21) (0.186 gm., 0.51 mmol, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:9][O:8][C:5]1[C:4]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:3][C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ncc(Br)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccccc2)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 100 °C

Procedure:
A solution of N-(5-bromo-2-methoxy-pyridin-3-ylmethyl)-N-(4-p-tolyloxy-phenyl)-methanesulfonamide (0.16 g, 0.33 mmol) from Example 49 Step A and phenyl boronic acid (0.059 g, 0.49 mmol) in dioxane/H2O (2 mL/0.5 mL) was treated with Na2CO3 (0.11 g, 1.0 mmol) and PdCl2dppf.CH2Cl2 complex (23.8 mg, 0.033 mmol). The resulting mixture was heated at 100° C. overnight. The reaction mixture was brought to the usual work-up and the crude product was purified by chromatography (silica gel, 35% EtOAc/hexanes) to give the desired product. MS (EI) 475 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:10]=[C:11](/[CH:13]=[C:14](\C)/[C:15]([O:17][CH3:18])=[O:16])[N:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH2:41]Br)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH2:41][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:10]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[N:12]=3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(O)cc2)n1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Product: COC(=O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n1
Yield: 73.2 %

Procedure:
According to the procedure for preparation of 4.4, phenol 12.9 (60 mg, 0.184 mmol) was alkylated with (4′-chloro-4-methoxy-1,1′-biphenyl-2-yl)methyl bromide (63 mg, 0.202 mmol), to yield 75 mg (73%) of 12.10. MS (ESI) 557.4 (MH+).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[N:14]1[C:21]([Cl:22])=[N:20][C:18](Cl)=[N:17][C:15]=1[Cl:16]>CC(C)=O>[Cl:16][C:15]1[N:14]=[C:21]([Cl:22])[N:20]=[C:18]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:17]=1
Reactant: Oc1cccc2ccccc12
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Oc2cccc3ccccc23)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 2 l round-bottom flask, 125.0 g of cyanuric chloride were dissolved in 300 ml of acetone, and a solution of 96.8 g of 1-naphthol in 300 ml of acetone was slowly added dropwise at 0° C. Subsequently, 168 ml of 4 N sodium hydroxide solution were slowly added dropwise. The mixture was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for a further 1 h. The aqueous phase was removed and 200 ml of 5% NaOH and 200 ml of chloroform were added to the organic phase, the aqueous phase was removed again and the organic phase was washed twice with 80 ml each time of 5% NaOH and three times with 180 ml each time of water, and dried over sodium sulfate. The mixture was filtered and the solvent was distilled off under reduced pressure. The product was obtained as a colorless solid (preparation described in WO 8704321).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([OH:12])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[CH2:17]([O:16][C:15]1[CH:14]=[CH:13][C:9]([C:10]([C:29]2[NH:28][CH:32]=[CH:31][CH:30]=2)=[O:12])=[CH:8][C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: c1cc[nH]c1
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1OCC(C)C
Agent: C[Mg]Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(C(=O)c2ccc[nH]2)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.0 g of 3-(3-ethoxy-3-oxopropyl)-4-isobutoxybenzoic acid in 80 ml of tetrahydrofuran are dropwise added 3.6 ml of oxalyl chloride and 60 μl of N,N-dimethylformamide successively, and the mixture thus obtained is stirred at ambient temperature for one hour. Then, to the reaction mixture obtained herein is dropwise added, at −70° C., a pyrrole reagent prepared from 8.5 ml of pyrrole and 82 ml of 1 mol/L solution of methylmagnesium bromide in tetrahydrofuran. After dropping, the temperature is elevated to ambient temperature over a period of one hour, and the mixture is stirred at ambient temperature for one hour. The reaction mixture is cooled with ice water, a saturated aqueous solution of ammonium chloride is dropwise added, the mixture thus obtained is stirred at ambient temperature for 15 minutes, ethyl acetate is added, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 5.0 g of ethyl 3-[2-isobutoxy-5-(1H-pyrrol-2-ylcarbonyl)phenyl]-propanoate as a brown-colored solid product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:13]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH2:13])=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Reactant: N
Solvent: CO
Product: NC(=S)Nc1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To 7.20 g (40 mmol) of 3-nitrophenylisothiocyanate in 25 mL of methanol was added 28.5 mL (200 mmol) of 7 N ammonia in methanol. After 30 min., the slurry was concentrated to give 7.9 g (100%) of the title compound as a yellow-orange powder that did not require further purification.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.[CH2:13]([O:15][C:16](=[O:28])/[C:17](=[CH:24]/OCC)/[C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH3:14]>CCO>[F:20][C:19]([F:22])([F:21])[C:18]1[NH:3][N:2]=[CH:24][C:17]=1[C:16]([O:15][CH2:13][CH3:14])=[O:28]
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 147 mmol) in EtOH (500 mL), DIPEA (45.3 mL, 267 mmol) was added slowly at −20° C. and stirred for 10 minutes. Then 2-[1-ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (Preparation 96 Step 1, 32 g, 133.33 mmol) was added to above solution and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (25 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with Hexane:EtOAc 90:10 to afford the title compound as off white solid (43%, 13 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][O:7][CH:6]1[O:10][CH3:11])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:11][O:10][CH:6]1[CH:5]([CH2:3][OH:2])[CH2:9][CH2:8][O:7]1
Reactant: COC(=O)C1CCOC1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC1OCCC1CO
Yield: 84.7 %

Procedure:
To a solution of 2-methoxy-tetrahydro-furan-3-carboxylic acid methyl ester (10 g, 62.5 mmol) in 60 ml of dry THF was added 4.75 g (125 mmol) LiAlH4 at 25° C. The mixture was refluxed for 4 hrs and cooled. 4.75 ml of H2O and 4.75 ml of aq. NaOH(10%) were added to the reaction mixture in turn. The resulting mixture was filtered and the filtrate was concentrated to yield (2-methoxy-tetrahydro-furan-3-yl)-methanol (7 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@@H:39]5[CH2:48][CH3:49])=[CH:34][N:33]=4)[C:28](=[O:50])[N:27]([CH3:51])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@@H:39]5[CH2:48][CH3:49])=[CH:34][N:33]=4)[C:28](=[O:50])[N:27]([CH3:51])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of 112a (140 mg, 0.20 mmol), NaBH4 (21 mg, 0.60) and CH3OH (8 mL) was stirred at 25° C. for 1 h. Then the reaction mixture was quenched with water (10 mL), the mixture was extracted with CH2Cl2 (15 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 112 (70 mg, 50%). LCMS: [M+H]+ 695. 1H NMR (500 MHz, DMSO) δ 8.50-8.60 (m, 2H), 8.44 (s, 1H), 7.90 (d, J=1.5, 1H), 7.82 (d, J=3.0, 1H), 7.75-7.78 (m, 1H), 7.51-7.53 (m, 1H), 7.45 (d, J=2.5, 1H), 7.33-7.35 (m, 1H), 7.22-7.24 (m, 1H), 4.47-4.59 (m, 2H), 4.36-4.45 (m, 4H), 3.60 (s, 3H), 3.46-3.50 (m, 1H), 3.38-3.41 (m, 3H), 3.14-3.17 (m, 1H), 2.96-3.00 (m, 1H), 2.60-2.64 (m, 1H), 2.50-2.55 (m, 1H), 2.14-2.17 (m, 1H), 2.06-2.10 (m, 1H), 1.66-1.69 (m, 1H), 1.39 (s, 9H), 1.21-1.28 (m, 1H), 0.77-0.80 (m, 3H)
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[Br:28][C:29]1[N:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[OH-].[Na+].[Cl-].[NH4+]>C(O)C.C(O)(=O)C>[Br:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][NH:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=4)[NH:10][CH:11]=3)=[CH:26][N:25]=2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1cnc2[nH]cc(Cc3ccc(NCc4ccc(Br)nc4)nc3)c2c1
Temperature: 110 °C
Yield: 31 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (120, 80.0 mg, 0.200 mmol) in 2.00 mL of ethanol and 0.10 mL of acetic acid, 6-bromo-pyridine-3-carbaldehyde (121, 100.0 mg, 0.538 mmol) and silica supported cyanoborohydride (0.50 g, 1.21 mmol/g) were added. The reaction was heated at 110° C. for 25 minutes in microwave. Sodium hydroxide (2.0 mL, 6.0 M aqueous) was added and the reaction heated at 100° C. for 10 minutes in microwave, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (P-2002, 26.6 mg). MS (ESI) [M+H+]+=427.7, 429.7.
Reaction SMILES: CCCCOC([NH:8][C:9]([C@@H:11]([NH:19][C:20]([C@@H:22]([NH:27][C:28]([C@@H:30]([NH:35][C:36]([C@@H:38]([NH2:49])[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:37])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.Cl>O1CCOCC1.CCOCC>[NH2:49][C@H:38]([C:36]([NH:35][C@H:30]([C:28]([NH:27][C@H:22]([C:20]([NH:19][C@H:11]([C:9]([NH2:8])=[O:10])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[CH2:23][C:24](=[O:25])[OH:26])=[O:29])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1
Reactant: CCCCOC(=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 0.05 h

Procedure:
7.1 g (10.5 mmoles) of BOC--Trp--Leu--Asp--Phe--NH2, prepared as described in Example 5, Step 2, are poured into 60 ml of hydrochloric acid in dioxane. The reaction mixture is initially turbid, but it gets clear within 3 minutes. After 10 minutes the solution is diluted with dry ether, the separated oily substance is solidified and filtered off. The resulting 6.96 g of hydrochloride are dissolved in 150 ml of warm water. Te pH of the solution is adjusted to 7 with solid sodium bicarbonate under cooling. The resulting suspension is filtered, and the precipitate is washed with a great proportion of water. 5.05 g (83.1 %) of H--Trp--Leu--Asp--Phe--NH2 are obtained; the chromatographically uniform substance melts at 228°-230° C. (decomposition). The product is identical with that obtained in Example 4, Step 4.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:16])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:1][C:2]1[C:9]([C:10]#[CH:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:16])[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cc(C#N)c(Cl)cc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(C#N)c(Cl)cc1N
Temperature: 75 °C
Yield: 99.1 %

Procedure:
To a solution of 238 (1.0 g, 4 mmol) in THF (100 mL) was added tetrabutylammonium fluoride (2.0 g, 7.6 mmol). The mixture was heated at 75° C. overnight then concentrated and the residue partitioned between EtOAc (500 mL) and H2O (50 mL). The organic layer was separated, washed with brine, concentrated to dryness in vacuo. The crude was purified by CombiFlash chromatography eluting with an EtOAc/petroleum ether gradient (10% to 45% EtOAc) to afford 700 mg (48%) 4-amino-2-chloro-5-ethynylbenzonitrile (240) as yellow solid: MS (ESI) m/z=177.0 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][N:15]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[C:24]([CH3:31])=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=1>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]2[NH:29][C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:19]=3)=[N:30][C:25]=2[C:24]=1[CH3:31]
Reactant: CN1CCCN(CCCCOc2cc(C=O)ccn2)CC1
Reactant: Cc1c(F)ccc(N)c1N
Solvent: CN(C)C=O
Product: Cc1c(F)ccc2[nH]c(-c3ccnc(OCCCCN4CCCN(C)CC4)c3)nc12
Yield: 5.6 %

Procedure:
5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole. To a stirred solution of 2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-isonicotinonitrile (1.0 g, 3.47 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in toluene (5.2 mL, 5.2 mmol, 1.5 equiv). After 3 h, methanol (9 mL) and 1.0 M H2SO4 (10 mL) were added. The mixture was stirred for 30 min, and then 1.0 M NaOH (10 mL) was added, followed by satd. aq. sodium potassium tartrate (40 mL) and dichloromethane (100 mL). After stirring for 30 min, the mixture was extracted with chloroform (3×50 mL) and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was partially purified by Method 2 to afford 268 mg of a mixture of 2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridine-4-carbaldehyde and several other unidentified products. A portion of the impure 2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridine-4-carbaldehyde (63 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (30.3 mg), and Na2S2O5 (53.4 mg) were stirred in DMF (3 mL) at 90° C. for 18 h. The reaction mixture was loaded directly on silica gel and purified by Method 2, which afforded 5.0 mg of the title compound. MS (electrospray): mass calculated for C23H30FN5O, 411.24; m/z found, 412.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.27 (dd, J=4.8, 0.5 Hz, 1H), 7.63 (dd, J=4.0, 1.4 Hz, 1H), 7.52-7.40 (m, 2H), 7.10-7.01 (m, 1H), 4.27 (t, J=6.3 Hz, 2H), 2.86-2.77 (m, 4H), 2.77-2.68 (m, 4H), 2.65-2.57 (m, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.90-1.66 (m, 6H).