Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][C:7]=1[S:18]([Cl:17])(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
A mixture of 4-fluoro-1-nitro-2-[(2,2,2-trifluoroethyl)oxy]benzene (10 g, 41.8 mmol) in chlorosulfonic acid (82 mL, 125.5 mmol) was stirred at 50° C. for 8 hours before being poured into ice and extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated to give 2-fluoro-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonyl chloride (15 g, crude) as a brown oil, which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])[N:11]=2)[CH:5]=1)[CH3:2].[CH2:29](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:13][CH:14]=[C:15]3[N:16]=[CH:29]2)[CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCOc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](C)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-(5-Ethoxy-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 29, 0.3 g) was dissolved into ethanol (20 mL) with Pd—C (90 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.034 g desired product. MS (electrospray): 368 (M+1) for C18H18FN7O. 1H NMR (300 MHz, CD3OD) δ ppm 8.30 (s, 1H) 8.20 (s, 1H) 7.70 (d, 1H) 7.40 (d, 1H) 6.60 (d, 1H) 5.90 (s, 1H) 5.10 (m, 1H) 4.10 (q, 2H) 1.50 (d, 3H) 1.40 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[S:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH:36][C:14]([C:12]3[S:13][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)=[O:16])[NH:34][N:35]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: CCOC(=O)c1ccc(N2CCCN(C)CC2)s1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (0.201 g, 0.75 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.185 g, 0.75 mmol) in toluene (10 mL) were stirred at 20° C. and a 2M solution of trimethylaluminium in toluene (0.938 mL, 1.88 mmol) was added drop-wise. The reaction stirred under nitrogen at 60° C. for 18 h. The reaction mixture was cooled and quenched by pouring into methanol (50 ml), acidified with few drops of 2N hydrochloric acid. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[NH:24][C:23]4[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=4[N:17]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:24]([CH3:33])[C:23]4[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[N:19]([CH2:30][CH2:31][CH3:32])[C:18]=4[N:17]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4ccc(F)cc4)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)n2C)n(CCC)c1=O
Temperature: 50 °C

Procedure:
A mixture of 8-{1-[3-(4-fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (0.035 g, 0.08 mmol), potassium carbonate (0.022 g, 0.16 mmol), methyl iodide (0.005 ml, 0.088 mmol) and DMF (2 ml) were heated at 50° C. for 20 hour. The mixture was cooled to room temperature and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and sat. brine solution, and dried over Na2SO4. Solvent was evaporated, the residue obtained was triturated with hexane to obtain the title compound (0.022 g, 61
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])=[C:9]([CH:31]([CH3:33])[CH3:32])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[CH3:34]O[N-]C.[CH2:38](O)[CH3:39].[OH-].[Na+]>O>[CH:9]([NH:8][CH:38]([CH3:39])[CH3:34])([CH3:31])[CH3:10].[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:10](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])=[C:9]([CH:31]([CH3:33])[CH3:32])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: C[N-]OC
Reactant: CCO
Agent: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(C)C
Reaction time: 16 h

Procedure:
E-(7-{2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl}-[(3R,5S)-3,5-dihydroxy-hept-6-enoic acid])-N-methoxy-N-methyl-amide (38.3 g), ethyl alcohol (300.0 mL), and a solution of sodium hydroxide (5.1 g) in water (60.0 mL) were added to a reactor. The reaction mixture was stirred for 16 hours while maintaining the temperature of 20˜25° C., and then concentrated under reduced pressure. Ethyl acetate (240.0 mL) and water (360.0 mL) were added to the resulting residue under stirring. Ethyl acetate (240.0 mL) was added to the separated water layer, which was then adjusted to pH 3.0˜4.0 using 1N hydrochloric acid solution. The separated organic layer was concentrated under reduced pressure. Tetrahydrofuran (900.0 mL) and diisopropylamine (12.0 mL) were added to the resulting residue. The reaction mixture was stirred at 20˜25° C. for over 12 hours and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain E-7-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid diisopropylamine salt (38.0 g, yield 90%, HPLC purity 99.7%).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11].N([O-])=O.[Na+].[Cu](C#N)[C:22]#[N:23].[C-]#N.[K+].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.O>[Cl:16][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[C:22]#[N:23]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: N#C[Cu]C#N
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1cc(C(=O)O)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a stirred mixture of conc. sulfuric acid (60 mL) and water (95 mL) containing 3-amino-4-chlorobenzoic acid (10.0 g, 57.1 mmol) was added sodium nitrite (10.0 g, 145 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours, and added to a stirred mixture comprising a mixture of water (250 mL) and benzene (175 mL) containing copper cyanide (7.1 g, 79.3 mmol), potassium cyanide (21.7 g, 333 mmol), potassium carbonate (285 g, 2.06 mmol) at a temperature not higher than 15° C. The resulting mixture was heated under stirring at 80° C. for one hour, cooled to room temperature, stirred under ice-cooling, and filtered using Celite to collect insolubles. The insolubles were washed with benzene (100 mL) and ether (100 mL). The aqueous portion was taken out, and made to pH 2 by addition of conc. hydrochloric acid under stirring and ice-cooling. The aqueous portion was subjected to extraction with ether (200 mL×2), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was repeatedly purified by silica gel column chromatography (ethyl acetate/hexane), to obtain 2.0 g (yield 19%) of the titled compound as a pale yellow crystalline product.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:2]=[N-:3].C(N(CC)CC)C.[O:20]1CC[CH2:22][CH2:21]1.C(Cl)(=O)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[N:1]([CH2:4][C@H:5]([O:12][C:21](=[O:20])[CH3:22])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:2]=[N-:3]
Reactant: C1CCOC1
Reactant: CCOC(=O)C[C@@H](O)CN=[N+]=[N-]
Agent: CN(C)c1ccncc1
Solvent: CC(=O)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](CN=[N+]=[N-])OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
In a 100 ml four-necked flask were charged 5.0 g (28.8 mmol) of ethyl (R)-4-azido-3-hydroxybutyrate, 3.5 g (34.6 mmol) of triethylamine, 0.11 g (0.900 mmol) of 4-dimethylaminopyridine and 50 ml of tetrahydrofuran, and after the mixture was cooled to 0° C., 2.50 g (31.8 mmol) of acetyl chloride was slowly added thereto dropwise in a nitrogen stream. After the addition, the reaction mixture was further stirred at room temperature overnight, and then the solvent was distilled under reduced pressure to give 4.94 g of a concentrate. The concentrate was subjected to column chromatography (ethyl acetate/hexane=1/10 by volume) to obtain 4.50 g (73%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[C:2]3[C:3](=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:10][CH:11]=3)[CH:12]=[C:13]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1ccc(Cl)c(C#Cc2ccc(F)cc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc2c(c1)cc(-c1ccc(F)cc1)n2-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an inert atmosphere of nitrogen, a mixture of methyl 4-chloro-3-(2-(4-fluorophenyl)ethynyl)benzoate (200 mg, 0.69 mmol, 1.00 equiv), 4-fluoroaniline (152.8 mg, 1.39 mmol, 2.00 equiv), X-Phos (65.2 mg, 0.14 mmol, 0.20 equiv), Pd2(dba)3 (63.8 mg, 0.07 mmol, 0.10 equiv), t-BuOK (388.8 mg, 3.47 mmol, 5.00 equiv), and toluene (8 mL) was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo, and purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:1)). The crude product (160 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (MS-Directed)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 70% in 10 min); Detector, UV 254 nm. This resulted in 26 mg (11%) of 1,2-bis(4-fluorophenyl)-1H-indole-5-carboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C)C=O.O>[N:13]1([CH2:12][C:10]2[C:9]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:11]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 2-hydroxy-4-(morpholinomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 48; 300 mg, 0.94 mmol) was taken up in N,N-dimethylformamide (5 ml) and cesium carbonate (340 mg, 1.04 mmol) and benzyl bromide (0.16 ml, 1.31 mmol) were added. The mixture was heated at 40° C. for 18 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer was separated and washed with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (1:1 cyclohexane/ethyl acetate-10% 7M NH3 in methanol/dichloromethane) gave the title compound as oil. 248 mg.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc(I)nc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg,1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphophine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidin-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=O)=[CH:21][CH:20]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(OCC(F)(F)C(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:26]2[N:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:34])([F:15])[CH:31]([F:32])[F:33])=[CH:24][CH:23]=3)[CH:29]=[CH:28][N:27]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nccn1-c1ccc(OCC(F)(F)C(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 11.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.72 g of 1-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-2(1H, 3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (0.21 g) and 0.14 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:64]=[C:63]([O:65][CH3:66])[C:51]([C:52]([NH:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[O:53])=[C:50]([F:67])[CH:49]=1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([CH2:55][NH:54][C:52](=[O:53])[C:51]2[C:63]([O:65][CH3:66])=[CH:64][C:48]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[CH:49][C:50]=2[F:67])=[CH:57][CH:58]=1
Reactant: C1COCCN1
Reactant: COc1cc(Br)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N2CCOCC2)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 120 °C
Yield: 42.6 %

Procedure:
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (468 mg, 0.75 mmol) is added to a stirred solution of 4-bromo-N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-benzamide (2.8 g, 7.52 mmol), morpholine (0.92 g, 10.5 mmol) and sodium tert-butoxide (0.94 g, 9.78 mmol) in toluene (90 ml) and the mixture is degassed and flushed with argon for 45 min. Tris(dibenzylideneacetone)-dipalladium(0) (344 mg, 0.38 mmol) is added and the mixture is heated at 120° C. for 16 h. The mixture is cooled to room temperature and diluted with water (50 ml). The mixture is extracted with ethyl acetate (2×30 ml). The combined organic layers are washed with water (30 ml), brine (40 ml), dried over anhydrous sodium sulfate and evaporated to get the crude which is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to yield N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-4-morpholin-4-yl-benzamide (1.3 g, 3.2 mmol, 33%).
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[C:19]([C:21]1[CH:40]=[CH:39][C:24]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I>[OH:8][C:7]1[N:2]([C:20]#[C:19][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])=[CH:39][CH:40]=2)[CH:3]=[N:4][C:5]2=[N:11][C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:6]=12
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OC
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 3.6 g (10 mmol) of well-dried 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 40 mL of dimethylformamide are added 4.0 g (13.19 mmol) of dimethyl N-(4-ethynylbenzoyl)-L-glutamate, 0.38 g of copper (I) iodide, 3 mL of triethylamine, and 1.0 g of tetrakis-(triphenylphosphine)palladium. This mixture is stirred at ambient temperatures for two hours and then poured into 500 mL of water. The solid is collected by filtration, air dried, and then refluxed in 200 mL of methanol. The mixture is cooled and the solid collected by filtration, dissolved in two liters of 10% methanol in methylene chloride, and chromatographed over silica. Initial black bands are rechromatographed and the combined colorless bands from the first and second runs are evaporated to give 3.5 g of dimethyl N-[4-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate which can be purified further by recrystallization from 50% methanol in methylene chloride.
Reaction SMILES: FC1C=CC(C(=O)CBr)=CC=1.[C:12]([CH:14]([CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].FC1C=CC(C2NC=C(C(OCC)=O)C=2)=CC=1.[H-].[Na+].[F:49][C:50]([F:62])([F:61])[C:51]1[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>CN(C)C=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:13]([S:57]([C:54]3[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:61])[F:62])=[CH:56][CH:55]=3)(=[O:59])=[O:58])[CH:12]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1
Agent: O=C(CBr)c1ccc(F)cc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedure as in Reference Example 1 was performed to synthesize ethyl 2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as in Reference Examples 2 and 3 were performed to synthesize ethyl 5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. Sodium hydride (60% in oil, 0.28 g) was added to a solution (20 mL) of ethyl 5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (1.49 g) in N,N-dimethylformamide under ice-cooling. The mixture was stirred at the same temperature for 15 min, 4-trifluoromethylbenzenesulfonyl chloride (1.85 g) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2) to give the title compound as crystals (yield 1.80 g, 64%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][C@@:8]12[CH2:13][CH:12]1[CH2:11][NH:10][C@H:9]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:29][N:30]([CH2:32][C:33]1[NH:37][N:36]=[N:35][C:34]=1[CH:38]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH2:6][O:7][C@@:8]12[CH2:13][CH:12]1[CH2:11][N:10]([CH2:38][C:34]1[N:35]=[N:36][NH:37][C:33]=1[CH2:32][N:30]([CH3:31])[CH3:29])[C@H:9]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cc(CO[C@@]23CC2CN[C@H]3c2ccccc2)cc(C(F)(F)F)c1
Reactant: CN(C)Cc1[nH]nnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: COCCOC
Product: CN(C)Cc1[nH]nnc1CN1CC2C[C@@]2(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To the starting material as a mixture of diastereomers, Example 6 and Example 7, one being (1S,2S)-1-(3,5-bis-trifluoromethyl-benzyloxy)-2-phenyl-3-aza-bicyclo[3.1.0]hexane, (0.10 g, 0.25 mmol) in DME (1.0 mL) was added 5-dimethylaminomethyl-1H-[1,2,3]triazole-4-carbaldehyde (˜50% pure, 0.15 g, 0.45 mmol) mmol and the mixture stirred at room temperature for 1.5 hours. To the reaction flask was added sodium triacetoxyborohydride (0.10 g, 0.50 mmol) and stirring was continued for 64 hours. The reaction flask was placed in a 0° C. bath and to the reaction flask was added 1N HCl (2 mL) and the mixture stirred for 4 hours at room temperature. 1 N NaOH solution was added and then saturated sodium bicarbonate solution was added until the pH=8. The reaction mixture was extracted with methylene chloride, the organics washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. The crude product was purified by flash chromatography using elution with a gradient of 30% EtOAc/Hexanes to 100% EtOAc to give as the more polar diastereomer of the title compound. (0.034 g, 25% yield).).