Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=2)=[O:18])=[CH:15][C:14]=1I>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([C:32]([F:34])([F:33])[F:35])[CH:21]=2)=[O:18])=[CH:36][C:37]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The title compound was obtained as a light yellow solid. Mp: 153-155° C.; 1H NMR (300 MHz, CDCl3) δ: 9.39 (1 H, s), 8.49 (1 H, d, J=3.3 Hz), 8.08-8.18 (4 H, m), 7.91-7.94 (2 H, m), 7.57-7.60 (2 H, m), 7.34 (1 H, brs), 7.14-7.16 (1 H, m), 6.85 (1 H, brs), 2.28 (3 H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C26H17ClF3N6O: 521.1099. found: 521.1092.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To an N,N-dimethylformamide solution (400 ml) of 4-bromo-2-fluorobenzoic acid (50.3 g) were added at room temperature potassium carbonate (63.5 g) and benzyl bromide (27.3 ml), followed by stirring at 60° C. for 3 hours. After the precipitate was filtered off, the filtrate was concentrated to 100 ml, and then diluted with ethyl acetate. This was washed sequentially with a saturated aqueous ammonium chloride solution, water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford benzyl 4-bromo-2-fluorobenzoate (70.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:32][C@H:33]1[C@@H:40]2[N:36]([C:37](=[O:54])N(C3C4CCCCC=4C(C#N)=CC=3)[C:39]2=[O:41])[CH2:35][CH2:34]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[C:3]([C:1]#[N:2])=[CH:9][CH:8]=[C:6]([N:7]3[C:39](=[O:41])[C@@H:40]4[C@H:33]([OH:32])[CH2:34][CH2:35][N:36]4[C:37]3=[O:54])[CH:5]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ccc(N)cc1-c1ccc(F)cc1
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from compound 48A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 99% at 3.32 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm.). LC/MS m/z 352 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][N:15]=2)[C:11]=1O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[N:10]2[N:13]=[CH:14][N:15]=[C:9]2[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cnc2ncnn2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ncnn2c1Cl

Procedure:
A suspension of 6-ethoxycarbonyl-7-hydroxy-s-triazolo [1,5-a]pyrimidine (7 g) in phosphorus oxychloride (20 ml) was refluxed for 30 minutes, the resultant orange solution was further refluxed for one hour, and excess phosphorus oxychloride was removed by distillation under reduced pressure. Benzene (50 ml) was added to the residue, and remaining phosphorus oxychloride was completely removed by azeotropic distillation under reduced pressure. Chloroform (80 ml) was added to the residue, the insoluble matters were filtered off, and the solvent was removed in vacuo from the filtrate. Purification of the brown residue by silica gel column chromatography gave 3.9 g of the objective compound as colorless crystals.
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]([OH:23])=O.[CH3:24][O:25][C:26](=[O:53])[C@@H:27]([NH:32][C:33]([N:35]1[CH2:41][CH:40]([OH:42])[C@@H:39]([NH:43][C:44](=[O:51])[C@@H:45]([NH2:50])[CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:38][CH2:37][C@H:36]1[CH3:52])=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:24][O:25][C:26](=[O:53])[C@@H:27]([NH:32][C:33]([N:35]1[CH2:41][C@H:40]([OH:42])[C@@H:39]([NH:43][C:44](=[O:51])[C@@H:45]([NH:50][C:21]([C:13]2[O:12][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=2)=[O:23])[CH2:46][CH:47]([CH3:48])[CH3:49])[CH2:38][CH2:37][C@H:36]1[CH3:52])=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC[C@H]1C
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1C[C@H](O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)c2cc3ccccc3o2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (214 g, 1.12 mmol) was added to a solution of benzofuran-2-carboxylic acid (166 g, 1.02 mmol), (S)-2-({1-[(2R,5S)-5-((S)-2-Amino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoic acid methyl ester (430 mg, 0.93 mmol), diisopropylethylamine (240 mg, 0.32 ml, 1.86 mmol), hydroxybenztriazole (151 mg, 1.12 mmol) in DMF (5 ml) and was stirred at RT overnight. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 ml), washed with cold aq. 1N HCl, aq. sat. NaHCO3, and brine, and then dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2% to 3% MeOH/CH2Cl2) to yield the title compound (478 mg, 84% for two steps): electrospray MS: 572.4
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.C[Si]([N-:17][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[NH2:17][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Clc1nsnc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nsnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
3-Chloro-4-phenyl-1,2,5-thiadiazole (3.19 g, 16.2 mmol) in THF (32 ml) at 0° C. was treated d with a solution of lithium bis(trimethylsilyl)amide in THF (17.0 ml, 1.0 M, 17.0 mmol). After 10 min the mixture allowed to warm to ambient temperature for 1.5 hr, treated with 1N hydrochloric acid, and extracted three times into ether (total 300 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol (50 ml) and triethylamine (0.5 ml) was heated to reflux for 15 hr and again concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 3-amino-4-phenyl-1,2,5-thiadiazole (1.96 g, 68%) as a colorless solid.
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]=[C:15]3[NH:20][CH2:21][CH2:22][N:14]3[C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]=[C:15]3[NH:20][CH2:21][CH2:22][N:14]3[C:13]=2[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2nc3n(c2n(C)c1=O)CCN3
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2nc3n(c2n(C)c1=O)CCN3
Yield: 45.5 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1-methyl-1,6,7,8-tetrahydro-2H-imidazo[1,2-e]-purine-2,4(3H)-dione (100 mg, 0.286 mmol) and a 1.0 M solution of hydrogen chloride in diethyl ether (1 ml, 1.0 mmol) in methanol (25 ml) was stirred at room temperature overnight. After concentrating under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol-chloroform (4:2:1) to provide (R)-3-(5-hydroxyhexyl)-1-methyl-1,6,7,8-tetrahydro-2H-imidazo[1,2-e]-purine-2,4(3H)-dione (CT-30268) (40 mg, 46% yield) as a white powder.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[O:18]1[CH2:17][CH2:16][N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:20][CH2:19]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCOCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCOCC2)CC1

Procedure:
7.2 g (16.4 mmol) trans-dibenzyl-4-morpholino-cyclohexylamine were dissolved in 100 mL methanol and hydrogenated on 1.4 g Pd/C (10%) at 30-50° C. The solvent was eliminated in vacuo and the residue was crystallised from ethanol and conc. hydrochloric acid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][CH:30]=[O:31])=[C:19]([CH3:32])[CH:18]=1>C1COCC1.CCCCCC>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][CH:30]([OH:31])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:19]([CH3:32])[CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(Cl)c2ccc(Cl)cc2c1CCC=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CC(O)CCc1c(C)cc(Cl)c2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (0.292 g, 2.64 mmoles) dissolved in dry THF (2 ml) is added dropwise via a syringe through a septum to a stirred suspension of sodium hydride (0.127 g of a 50% NaH in mineral oil, 2.64 mmoles) in dry THF (7 ml) which had been chilled in an ice-water bath. The reaction was stirred in the cold for 15 minutes at which time a clear solution was obtained. To this solution in the cold was added n-butyl lithium (1.80 ml of a 1.47M solution in hexane; 2.64 mmoles) via syringe through the septum dropwise in about 5 minutes. The orange solution is stirred with ice-water bath for 15 minutes and then cooled to -78° C. in a dry ice-acetone bath. To this cold stirred reaction was added dropwise via syringe, 3-(4,7-dichloro-2-methylnaphthalen-1-yl)propanal (0.6715 g, 2.513 mmoles) dissolved in dry THF (5 ml). The reaction is allowed to stir at -78° for 15 minutes, then allowed to warm to 0° by emersing the reaction flask in an ice-water bath. When ice separated from the flask, the reaction was worked up by partitioning it between ether (150 ml) and water containing 0.6 ml of 12N HCl. Extracted the water layer with ether. The combined ether extracts are washed with water twice then with saturated solution of NaHCO3. The ether was dried (MgSO4) and the solvent removed in vacuo to leave 0.96 g of crude title Rf =0.45 (silica, 5% acetone/CH2Cl2) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10]C(=O)C.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(F)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(F)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A solution of N-(2-chloro-4,5-difluorophenyl)acetamide (4.69 g, 22.8 mmol) in acetic acid (4.5 mL) and concentrated sulfuric acid (15 ml) was cooled to 0° C. To the solution was added a mixture of fuming nitric acid (2 mL) and acetic acid (0.5 mL). After stirring for 1.5 h at 0° C., the mixture was poured into ice. A precipitate formed, and it was collected by filtration. The filtrate was extracted with ether, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to sticky yellow syrup. The solid and the syrup were combined, and to the resulting residue was added concentrated hydrochloric acid (30 mL). This mixture was heated to 120° C. for 1.25 h. It was then cooled to rt and subsequently poured onto ice. The aqueous solution was extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (80% hexanes:20% ethyl acetate) to provide the desired 6-chloro-3,4-difluoro-2-nitroaniline (3.30 g, 15.8 mmol, 69% yield). 1H NMR (400 MHz, CDCl3): 7.43 (dd, 1H), 5.86 (br s, 2H); GCMS for C6H3ClF2N2O2: 208 (M+).
Reaction SMILES: II.Br[C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([O:10][CH3:11])[CH:9]=1.[C:13]1([P:19](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCCC1.C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([P:19](=[O:20])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: COc1cc(Br)ccc1Cl
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(P(=O)(c2ccccc2)c2ccccc2)ccc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Under argon, 1 mol of Mg turnings and a spatula tip of iodine in a mixture of 100 ml of tetrahydrofuran and 100 ml of toluene were heated to 60° C. Over the course of 10 minutes, 200 g of 5-bromo-2-chloroanisole in a mixture of 200 ml of tetrahydrofuran and 200 ml of toluene were added dropwise. During the dropwise addition, the internal temperature was maintained at 60° C. by cooling. When the dropwise addition was complete, the reaction mixture was heated to reflux temperature and after-stirred for 30 minutes at this temperature. The mixture was then cooled to 0° C. and 236.8 g of diphenylphosphinic chloride were added dropwise over the course of 45 minutes. The internal temperature was maintained during this operation between 0 and 5° C. The reaction mixture was after-stirred for 5 minutes at 0° C., the cooling was switched off, and the mixture was stirred for a further 2 hours. For work-up, the reaction mixture was poured onto 1.6 liter of iced water, the organic phase was separated off, and the aqueous phase was washed again with 2×400 ml of toluene. The combined organic phases were washed with 400 ml of 2.5% strength by weight aqueous soda solution and then with 400 ml of water, and then concentrated on a rotary evaporator to a volume of 200 ml. Then, with stirring, 300 ml of n-pentane were added dropwise. The solid that precipitated out overnight was filtered off with suction, washed with n-pentane, and dried. This gave 203.5 g of a white solid. The yield was 82% and the purity was 94%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[I:21][Si](C)(C)C.II.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O1CCCC1>[I:21][CH:9]1[CH2:8][CH2:7][C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: C[Si](C)(C)I
Reactant: O=C1CCCc2cc(F)ccc2N1
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(F)cc2CCC1I
Temperature: -15 °C
Yield: 73 %

Procedure:
7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (411 mg, 2.3 mmol) (Step A) dissolved in a mixture of 7.9 mL of dry methylene chloride and 1.0 mL of dry tetrahydrofuran was treated with 1.62 mL (1.18 g, 11.6 mmol, 5 eq) of triethylamine and the resulting solution cooled to -15° C. Iodotrimethylsilane (0.66 mL, 932 mg, 4.7 mmol, 2 eq) was added followed by 1.183 g of iodine (4.7 mmol, 2 eq) added in small portions over 5 minutes. The mixture was warmed to room temperature over 5 minutes at which time 15 mL of methylene chloride was added followed by 20 mL of 10% aqueous sodium sulfite. The layers were separated and the organic layer washed with 10% sodium sulfite (3×20 mL). The aqueous layer was further extracted with 20 mL of methylene chloride. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The crude product was chromatographed on silica gel, eluting with methylene chloride/methanol (99:1) to afford 511 mg (1.68 mmol, 73%) of the product. 1H NMR (300 MHz, CDCl3): 2.70 (m,3H), 2.93 (m,1H), 4.62 (t,9 Hz,1H), 6.95 (m,3H), 7.86 (br s,1H). FAB-MS: calculated for C10H9FINO 305; found 306 (M+H,100%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:25])[NH:6][C:7](=[O:24])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:2].[CH3:26][CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=2[O:28]1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[C:5]([CH3:25])[N:6]([C:33]2[CH:34]=[CH:35][C:29]3[O:28][CH:27]([CH3:26])[CH2:31][C:30]=3[CH:32]=2)[C:7](=[O:24])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
A mixture of 4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.99 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.98 g), molecular sieves 4 A (0.49 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.08 g, 78%).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][CH:20]([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.O1POPOP1>C(Cl)Cl>[F:19][CH:20]([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:24]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ccccc1C(F)F
Agent: Cl
Agent: O1POPOP1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 100 mg, 0.35 mmol), 2-(difluoromethyl)benzoic acid (CAS number 799814-32-7; 61 mg, 0.35 mmol) and triethylamine (0.148 ml, 1.06 mmol) in DCM (2 ml) was added 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tripropyl-, 2,4,6-trioxide (CAS number 68957-94-8; 50% in ethyl acetate, 0.417 ml, 0.71 mmol). The reaction mixture was stirred at room temperature for 3 hours. To this was then added further 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tripropyl-, 2,4,6-trioxide (CAS number 68957-94-8; 50% in ethyl acetate, 0.417 ml, 0.71 mmol) and stirred at room temperature overnight. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then triturated with diethyl ether to afford the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:1]([C:3]1([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of tert-butyl 4-cyanopiperidine-1-carboxylate (7 g; 33.29 mmol) and 2-chloro-3-fluoropyridine (4.82 g; 36.62 mmol) in toluene (40 ml) cooled in an acetone/ice bath under a nitrogen atmosphere, was added a solution of potassium bis(trimethylsilyl)amide (0.5M in toluene; 79.9 ml; 39.95 mmol) over 30 minutes keeping the internal temperature below −10° C. The reaction mixture was then allowed to warm to ambient temperature with stirring for 2 hours. The reaction was poured into brine (150 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO4, filtered and evaporated to give a brown oil. The crude product was chromatographed on silica gel eluted with 10% EtOAc in DCM to give the desired product a colourless oil. (4.8 g)
Reaction SMILES: N1C=CN=C1.[C:6]1([CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[OH:7].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O.O>[Si:14]([O:7][C:6]1[CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1

Procedure:
A solution of 2.9 parts of imidazole, 1.99 parts of hydroquinone and 3 parts of tert-butyldimethylsilyl chloride in 10 mL of dimetylformamide was stirred at room temperature for 1 hr 45 min. The reaction was monitored by TLC showed formation of product. The reaction mixture was diluted with 50 mL of deionized water and product was extracted with 2×50 mL of ether. The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel with 5% ethyl acetate-hexanes to yield 2.24 parts 4-(tert-butyldimethylsilyloxy)phenol. NMR was used to confirm the following structure.