Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Si](C)(C)C)[S:4][C:3]=1[C:11]1[S:12][C:13]([Si](C)(C)C)=[CH:14][C:15]=1Br.C([Li])CCC.Cl[Si:27](Cl)([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>O1CCCC1.CCCCCC>[CH2:34]([Si:27]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:11]2[S:12][CH:13]=[CH:14][C:15]1=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Reactant: CCCCCC[Si](Cl)(Cl)CCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC[Si]1(CCCCCC)c2ccsc2-c2sccc21
Temperature: -78 °C
Yield: 92.5 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound E4, synthesized in accordance with WO 2010/136353, 10.0 g) was placed in a 200 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (150 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.64 M, 27.5 mL) was added dropwise. After about 30 minutes of agitation, dichlorodi-n-hexylsilane (5.7 g) was added dropwise. The temperature was gradually raised to room temperature over the course of about 2 hours, after which water was added, and the product was extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by filtration. The resulting yellow-orange oily substance was dissolved in hexane (100 mL) and chloroform (50 mL), trifluoroacetic acid (5 mL) with the internal temperature at 2° C., and after 10 minutes of agitation water was added, and the organic layer was washed, dried with anhydrous sodium sulfate, and then concentrated by filtration. Heptane (70 mL) was added to the reaction solution, which was then concentrated under reduced pressure. The resulting yellow-green oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4,4-di-n-hexyl-dithieno[3,2-b:2′,3′-d]silole (Compound E19, 7.1 g, yield 91%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>[OH-].[OH-].[Pd+2].C1(C)C=CC=CC=1>[CH3:15][NH:14][C:12]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1
Reactant: [O-]B([O-])Oc1ccccc1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNc1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 4.5 h
Yield: 77.7 %

Procedure:
50 ml of a 2N aqueous solution of sodium carbonate and 0.34 g of 20% w/w palladium hydroxide on charcoal were added to a solution of 5.0 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66) and 3.9 g of phenyl borate in 80 ml of a 1:1 by volume mixture of ethanol and toluene, and the resulting mixture was stirred at 105° C. for 4.5 hours. At the end of this time, the reaction mixture was filtered to remove the palladium hydroxide on charcoal. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 4.75 g of the title compound, melting at 98°-99° C.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)O.[OH-].[Na+]>FC(F)(F)C(O)=O>[NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
After dissolving 120 mg of t-butyl 4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added and extraction was performed with ethyl acetate. The extract was washed with saline and dried over sodium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. After adding 5 ml of tetrahydrofuran, 26 mg of acetic acid, 92 mg of sodium triacetoxyborohydride and 0.5 ml of formaldehyde (37% in water) to the residue, the mixture was stirred at room temperature for 10 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with saline and then passed through a glass filter coated with NH type silica gel. The silica gel was washed thoroughly with ethyl acetate, the ethyl acetate layers were combined and subjected to distillation under reduced pressure, and the residue was solidified with ethyl acetate and hexane to obtain 80 mg of a colorless powder.
Reaction SMILES: O.[Sn](Cl)Cl.[C:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:17]([N+:35]([O-])=O)=[CH:16][N:15]=2)=[N:11][CH:12]=1)#[N:6]>C(O)C>[NH2:35][C:17]1[C:18]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:19][C:14]([NH:13][C:10]2[CH:9]=[N:8][C:7]([C:5]#[N:6])=[CH:12][N:11]=2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Temperature: 70 °C
Yield: 91.4 %

Procedure:
Tin (II) chloride hydrate (678 mg, 5 eq) was added to a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (273 mg) in ethanol (20 mL). The mixture was heated at 70° C. for 30 minutes then cooled to room temperature and evaporated to dryness. The residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The suspension was filtered and the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to give crude tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (233 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][C:13](=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(C(=O)OCc2ccccc2)C1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)C1CCC(Nc2ccccc2)C1
Reaction time: 8 h

Procedure:
The mixture of 3-oxocyclopentanecarboxylic acid benzyl ester (150 mg), aniline (75 mg), glacial acetic acid (200 μL), and sodium triacetoxyborohydride (230 mg) in DCM (20 mL) was stirred overnight. Upon the addition of aq. potassium carbonate (1M, 30 mL), the mixture was extracted with ethyl acetate (30 ml×2). Organic layers were combined, washed with brine, and concentrated. Flash chromatography on silica (50% ethyl acetate in hexane) gave the product as an oil: MS (m+1)=282.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28](Cl)=[C:23]3[CH:22]=[N:21]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[OH:39].O>CN(C)C=O.C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:39][C:32]4[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=4[F:30])=[C:23]3[CH:22]=[N:21]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Oc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cc(F)c(F)cc4F)ncnc32)CC1
Temperature: 100 °C
Yield: 49 %

Procedure:
Potassium carbonate (53 mg, 0.39 mmol) was added to a solution of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 100 mg, 0.3 mmol) and 2,4,5-trifluoro-phenol (available from Alfa Aesar, Ward Hill, Mass., USA; 57 mg, 0.39 mmol) in dimethylformamide (5 mL). The reaction mixture was heated at 100° C. in an oil bath overnight, then it was cooled to room temperature, and water and diethyl ether were added. The aqueous phase was extracted twice with diethyl ether and three times with hexane. The combined organic phases were evaporated and the resulting residue was purified by C18 reversed phase HPLC using a gradient of 20-100% acetonitrile/water to give 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (66 mg, 50%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.06 (m, 2H), 2.18-2.34 (m, 2H), 2.90-3.06 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.02 (m, 1H), 7.09-7.21 (m, 2H), 8.16 (s, 1H), 8.49 (s, 1H). HRMS Calcd. for C21H23F3N5O3 (MH+): 450.1748. Found: 450.1745.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.O1CCCC1.CCCCCCC>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[B:23]([OH:24])[OH:22])=[O:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester (4.225 g, 16.23 mmol) in tetrahydrofuran (40 mL) was added triisopropylborate (9.00 mL, 39.0 mmol). The solution was cooled to −78° C. and lithium diisopropylamide (12.0 mL of a 2.0M solution in tetrahydrofuran/heptane, 24.0 mmol) was added dropwise over 5 minutes. The red solution was stirred for 30 minutes, warmed to 0° C., and quenched by the slow addition of 1N hydrochloric acid (50 mL). The mixture was allowed to warm to room temperature, stirred for 30 minutes and added to hexanes (200 mL). The layers were separated and the organic layer was washed successively with 2N hydrochloric acid (two times with 100 mL), water (100 mL), and brine (50 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was crystallized from heptane (40 mL) to provide 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (3.037 g, 62% yield) as a white solid: mp=159-160° C.; IR 3377 (br), 2963, 1703, 1371, 1308, 1171, 1131, 794, 709 cm−1; 1H NMR (400 MHz, DMSO/D2O) δ 8.05 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 3.94 (s, 2H), 0.95 (s, 9H); 13C NMR (100 MHz, DMSO/D2O) δ 26.69, 31.69, 74.91, 125.29, 125.75, 128.30, 129.62, 131.98 (q, J=31.8 Hz), 136.28, 142.68, 166.90.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: O=C(O)CCC1CCC(=O)N1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C

Procedure:
A solution of 3.0 g (0.017 mol) L-Leucine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.05 ml (0.029 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred ten minutes, filtered and concentrated at reduced pressure. The oil is dissolved in 17 ml of dichloromethane and the following is added in a single addition: 4.35 g (0.021 mol) of dicyclohexylcarbodiimide; 100 mg (0.0008 mol) of 4-dimethylaminopyridine; 2.66 g (0.017 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 20 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 93:7 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 50 ° C. yields crystalline analytically pure (as a 0.33 hydrate) N-[1-oxo-3-(5-oxo-2-pyrrolidinyl) propyl]-L-leucine, methyl ester with a melting point of 70°-74.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8](=[CH:14][NH:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](Cl)[CH:3]=1.C(OCC)(=O)C.CCCCCC>CS(C)=O>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CNCC1CCCO1)C(=O)c1ccc(Br)cc1Cl
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CC2CCCO2)c2cc(Br)ccc2c1=O
Yield: 75.2 %

Procedure:
500 mg of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-[(tetrahydro-furan-2-ylmethyl)-amino]- acrylate and 148 mg of potassium t-butylate are held at 60° in 20 ml of DMSO for 30 mins. After chromatography on silica gel with ethyl acetate/hexane 1:1 343 mg of ethyl 7-bromo-4-oxo-1-(tetrahydro-furan-2-ylmethyl)-1,4-dihydro-quinoline-3-carboxylate are isolated as a yellowish oil. Yield: 75%. Mass spectrum: peaks inter alia at m/e: 380 (M++H, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:10]#[N:11])[C:8]#[N:9].O.[NH2:13][NH2:14]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:10]([NH2:11])=[N:13][NH:14][C:8]=1[NH2:9]
Reactant: NN
Reactant: N#CC(C#N)c1ccccn1
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c(N)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 2-pyridin-2-yl-malononitrile (0.65 g, 4.59 mmol) and hydrazine hydrate (225 μL, 4.59 mmol) in EtOH (5 mL) was heated to reflux and stirred for 16 hours. The reaction mixture was cooled down to room temperature and filtered. The resulting solid was washed with Et2O to provide the title compound as a light tan solid (0.42 g, 52%). The filtrate was evaporated to dryness and purified by silica gel chromatography eluting with NH4OH:MeOH:CH2Cl2 (0.5:5:95) to give a further 63.3 mg (8%) of the desired product. MS (ES+) 176, (ES−) 174. δH (DMSO-d6) 5.45 (4H, br s), 6.98 (1H, t), 7.57 (1H, d), 7.69 (1H, t), 8.46 (1H, d), 10.55 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH:14]=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][NH:22][C:21]2[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCOCC1
Reactant: Nc1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(CNc2ccc(Br)cc2)CCOCC1
Temperature: 25 °C

Procedure:
A solution of (4-formyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (4.48 g, 19.5 mmol), 4-bromoaniline (3.38 g, 19.7 mmol), and acetic acid (1.2 mL, 21.2 mmol) in ethyl acetate (50 mL) contained in a 250 mL round bottom flask fitted with a reflux condenser and a Dean and Stark trap was heated at reflux under N2 blanket for 2 h then cooled to ambient temperature. Sodium cyanoborohydride (1.29 g, 19.5 mmol) was added and the mixture stirred over night. The reaction mixture was then washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), preabsorbed on silica gel and flash chromatographed (elution solvent: 10% (v/v) ethyl acetate/hexane) to isolate the desired product as 3.1 g of white solid foam. LRMS (ESI) m/z 385.0, 387.0 [(M+H)+, calcd for C17H26N2O3Br 386.3].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1
Reactant: N#CCc1ccc(Br)cn1
Agent: B
Solvent: C1CCOC1
Product: NCCc1ccc(Br)cn1
Reaction time: 24 h

Procedure:
To a stirred solution of (5-bromo-2-pyridinyl)acetonitrile (0.26 g, 0.94 mmole), in THF (20 mL) at RT was added 1M BH3.THF (5 mL, 5.0 mmole). After 24 h, H2O (10 mL) wash added dropwise to the reaction solution followed by 1M HCl (10 mL). After 1 h, the reaction solution was made basic by addition of 6M NaOH (2 mL). The reaction contents were concentrated under vacuum and extracted with EtOAc (3×50 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum affording the crude title compound as light orange solid which was used directly without further purification: LC-MS (ES) m/e 281 (M+H)+.
Reaction SMILES: C[CH:2]1[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])(C(O)=O)[C:6](=[O:19])[CH2:5][CH2:4][N:3]1C(=O)C1C=CC=CC=1.[ClH:28]>>[ClH:28].[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:7]1[C:6](=[O:19])[CH2:5][CH2:4][NH:3][CH2:2]1
Reactant: CC1N(C(=O)c2ccccc2)CCC(=O)C1(Cc1ccccc1Br)C(=O)O
Agent: Cl
Product: O=C1CCNCC1Cc1ccccc1Br
Yield: 77 %

Procedure:
The ketoester (18.5 g, 0.043 mol) from Example 101 was suspended in 6N hydrochloric acid and refluxed for 18 hours. The reaction was cooled and the benzoic acid was filtered and washed with water. The filtrate was washed with ether (2×75 ml) and the aqueous layer was concentrated under reduced pressure. The crude residue was crystallized from ethanol and ethyl ether to produce the title compound (10.1 g, 77%) as a white solid, mp 198°-200° C.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.CN([CH2:70][C:71]([NH:73][C@H:74]1[CH2:78]CN[CH2:75]1)=O)C(NC(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=NC(OCC1C=CC([N+]([O-])=O)=CC=1)=O>C(#N)C.O1CCCC1>[CH:3]([N:73]([CH2:71][CH3:70])[CH:74]([CH3:75])[CH3:78])([CH3:31])[CH3:4]
Reactant: CN(CC(=O)N[C@H]1CCNC1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.05 g) in anhydrous acetonitrile (10 ml), N,N'-carbonyldiimidazole (401 mg) was added, followed by stirring at room temperature. To the reaction mixture, N,N-diisopropylethylamine (392 μl) and a solution of the compound (2.02 g), which had been obtained in (2), in anhydrous tetrahydrofuran (15 ml) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (1.69 g) was obtained as an amorphous substance.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:28][CH:29]=1)[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)O)cc2)cc1
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
To a solution of 2-(4-acetylbenzoylamino)-N-(4-methoxyphenyl)benzamide (101 mg, 0.260 mmol) in methanol (5 mL) cooled to 0° C. was added sodium borohydride (17 mg, 0.46 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (1 mL), diluted with methylene chloride (30 mL), and washed with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate/75% hexanes to 50% ethyl acetate/50% hexanes) to give 85 mg (84%) of the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>C(O)C.CO.ClCCl>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]3[CH:2]=2)=[C:6]([CH3:16])[CH:7]=1
Reactant: Cc1cc(OCCCCl)ccc1C(=O)CBr
Reactant: Cc1ccnc(N)c1
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(OCCCCl)cc3C)nc2c1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (6.77 g) and 2-amino-4-picoline (2.4 g) in ethanol (22 mL) was heated at 72° C. for 10 hours. The reaction mixture was cooled to ambient temperature and dissolved in methanol/dichloromethane and treated with Dowex® 550A basic resin until the pH of the mixture was 7. The resin was removed via filtration and the filtrate evaporated. The title compound was precipitated from ethyl acetate upon addition of hexanes and used without further purification.