Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][C@H:17]([CH3:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:15][C@H:14]2[CH3:28])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClCCCl.O>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][NH:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][C@H:17]([CH3:19])[N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:15][C@H:14]2[CH3:28])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH3:35]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1N
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CNc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.105 g, 0.26 mmol) in 1,2-dichloroethane (2 mL) was added ethyl glyoxylate (0.050 mL, ˜0.5 mmol, 50% solution in toluene), acetic acid (0.016 mL, 0.28 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol). The reaction was stirred at ambient temperature for 18 hours. Additional ethyl glyoxylate (0.050 mL, ˜0.5 mmol, 50% solution in toluene) and acetic acid (0.016 mL, 0.28 mmol) were added and the reaction was warmed to reflux for 3 hours. The reaction was then cooled to ambient temperature, sodium cyanoborohydride (˜0.030 g, 0.48 mmol) was added and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel provided the title compound (0.085 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:16]COC[CH2:12]2)=[O:10])=[CH:5][CH:4]=1)#[CH:2].CN(C)C(=O)C1C=CC(C#C[Si](C)(C)C)=CC=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]([CH3:16])[CH3:12])=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)N2CCOCC2)cc1
Agent: CN(C)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Product: C#Cc1ccc(C(=O)N(C)C)cc1

Procedure:
The title compound is prepared in analogy to (4-ethynyl-phenyl)-morpholin-4-yl-methanone (Example 16c) from N,N-Dimethyl-4-trimethylsilanylethynyl-benzamide. 1H-NMR (300 MHz): 3.15 (s, 1H); 3.33-3.94 (br, 8H); 7.37 (d, J=6.6, 2H); 7.53 (d, J=6.6, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](OS(C(F)(F)F)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:3])[CH3:2].[C:27]1([C:33]#[CH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:34]#[C:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([CH:18]=1)[O:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C#Cc2ccccc2)c(OCC(=O)OC(C)(C)C)c1

Procedure:
A solution of t-butyl { 5-acetyl-2[(trifluoromethyl)sulfonyloxy]-phenoxy}acetate(1.0 g, 1.3 mmol) and phenylacetylene (0.33 mL, 3.0 mmol) in 20 mL triethylamine in a thick walled pyrex tube is degassed with nitrogen for 15 minutes. Bis(triphenylphosphine)-palladium(II) chloride (35 mg, 0.05 mmol) and copper (I) iodide (10 mg, 0.05 mmol) are added, and the vessel is sealed, and heated to 60° for 18 hours. After cooling, the triethylamine is removed in vacuo, and the residue is dissolved in ether (100 mL) and washed with 1 N HCl (1×100 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 5:1 hexane/EtOAc) yields t-butyl [5-acetyl-2-(2-phenylethynyl)-phenoxy]-acetate, along with 10% starting material. This mixture is carried on to the next step.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[N:21][CH:22]=1>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([Br:16])=[CH:22][N:21]=2)[CH2:25]1)=[O:9]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Product: O=C(c1ccccc1-c1ccccc1)N1CCC[C@@H](Nc2ncc(Br)cn2)C1

Procedure:
prepared by reaction of biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]1[CH3:11]>CO>[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]1[CH3:11]
Reactant: Cc1ncc(C=O)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(CO)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium borohydride (457 mg, 12.1 mmol) in methanol (25 mL) was added a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (1.0 g, 8.1 mmol) in methanol (10 mL) at 0° C. The mixture was stirred overnight at room temperature. The solvent was evaporated, and crude (1,2-dimethyl-1H-imidazol-5-yl)methanol was obtained and used in the next step without purification; 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 3.45 (s, 3H), 4.34 (s, 2H), 5.05 (bs, 1H), 6.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](CN3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)=[N:6][CH:7]=1.FC1C=CC([C:33]2C(CN3C(=O)C4C(=CC=CC=4)C3=O)=C(C)O[N:34]=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([NH:34][CH3:33])=[C:11]([CH3:25])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1onc(-c2ccc(Cl)cn2)c1CN1C(=O)c2ccccc2C1=O
Product: CNc1c(-c2ccc(Cl)cn2)noc1C
Yield: 69 %

Procedure:
As described for example 78b, 2-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (1.3 g, 3.68 mmol) was converted, instead of 2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione, to the title compound (570 mg, 69%) which was obtained as a white solid. MS: m/e=224.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(C(C)C)C(C)C)C.Cl[C:33]1[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:33]3[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=3)[CH:3]=2)=[O:22])[CH:16]=[CH:15][CH:14]=1)([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(1-cyano-1-methylethyl)benzamide (1.00 g, 3.41 mmol) in tetrahydrofuran (15 mL) were added N-ethyl-N-isopropylpropane-2-amine (893 μL, 5.11 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (812 mg, 3.75 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (1.41 g, 88%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH2:13]([N:4]1[C:3](=[O:16])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:19]=3[O:18][CH3:17])=[N:8][C:7]=2[N:6]([CH2:9][CH2:10][CH3:11])[C:5]1=[O:12])[CH2:14][CH3:15]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3OC)nc2n(CCC)c1=O
Yield: 48.5 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.00 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.32 g (9.73 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 1.84 g (yield 49%) of Compound 20 as pale yellow needles.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CN[C@H]1CCCC[C@@H]1NC>O1CCOCC1.[Cu]I>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([N:3]2[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:5][N:1]=[CH:2]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(I)cc1
Reactant: CCOC(=O)c1c[nH]cn1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cncn1-c1ccc(C#N)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
A mixture of ethyl 1H-imidazole-4-carboxylate (10 g, 71.36 mmol, 1.00 equiv), CuI (2.7 g, 14.18 mmol, 0.20 equiv), potassium carbonate (30 g, 217.06 mmol, 3.02 equiv), 4-iodobenzonitrile (25 g, 109.16 mmol, 1.53 equiv) and (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (2.0 g, 14.06 mmol, 0.20 equiv) in 1,4-dioxane (200 mL) was stirred under nitrogen at 95° C. overnight. The reaction was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with 800 mL of ethyl acetate then washed with 3×400 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 1-3% of methanol in dichloromethane to give 450 mg (3%) of ethyl 1-(4-cyanophenyl)-1H-imidazole-5-carboxylate as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 8.19 (d, J=0.9 Hz, 2H), 7.84 (d, J=0.9 Hz, 2H), 4.15 (q, J=5.4 Hz, 2H), 1.16 (t, J=5.1 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.19 min, m/z=242.0 [M+H]+ and 1.2 g (7%) of ethyl 1-(4-cyanophenyl)-1H-imidazole-4-carboxylate as a white solid. 1H-NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.82-7.76 (m, 3H), 7.50-7.47 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.16 min, m/z=242.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH3:10].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOC(C)=O>[Br:19][CH2:10][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=Cc1ccccc1Cl)c1ccc(F)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(C(=Cc2ccccc2Cl)CBr)c(F)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of 1-[1-(2-chlorophenyl)prop-1-en-2-yl]-2,4-difluorobenzene (680 mg, 2.56 mmol), N-bromosuccinimide (823 mg, 4.62 mmol) and benzoyl peroxide (30 mg) in AcOEt (15 ml) was heated under reflux for 3 h. After cooling to room temperature, the reaction mixture was diluted with AcOEt and washed with water, and the combined organic phases were dried and concentrated to dryness under reduced pressure. Purification by chromatography on silica gel gave 1-[3-bromo-1-(2-chlorophenyl)prop-1-en-2-yl]-2,4-difluorobenzene as a 52/48 mixture of diastereoisomers [colourless oil, 792 mg, yield 85%; GC/MS: m/z=344 (M+); HPLC/MS: log P(HCOOH)=4.80 (major diastereoisomer), 5.25 (minor diastereoisomer)].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([OH:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([C@H:30]([CH3:34])[C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([O:23][C:31](=[O:32])[C@H:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:34])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](C(=O)OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1 g (3.23 mmol) of 1-benzyl-4-(3-phenyl-2-hydroxypropyl)piperidine (Example 228, Step 2) and 0.775 g (5.16 mmol) of (S)-2-phenylpropionic acid in 10 mL of CH2Cl2 at 0° C. was added 1.32 g (6.9 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.1 g of 4-(dimethylamino)pyridine. The reaction was stirred for 5 h and let warm to rt. To the reaction mixture was added 80 mL of CH2Cl2 and the mixture was washed three times with 10% NaOH solution. The organic layer was washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 4:1) to give isomer 1a of the the title compound. Mass Spectrum (ESI) m/e=442 (M+1). [α]D=−3.7 (c=2.44, CHCl3).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCCCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCCCl)cc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-iodonitrobenzene (25 g, 100 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.30 g, 0.43 mmol) and copper (I) iodide (0.18 g, 0.95 mmol) in tetrahydrofuran (300 mL) and triethylamine (150 mL) was degassed under Argon for 10 minutes. The mixture was then heated to 55° C. and treated with 5-chloropentyne (12 mL, 110 mmol) via syringe. After 30 minutes of stirring, additional quantities of dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and 5-chloropentyne (1 mL) were added. After another 30 minutes of stirring, the mixture was allowed to cool to room temperature and then was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was carried on without further purification. ES/MS calcd. for C11H11ClNO2+ 224.1. found m/z=224.2 (M+1-1)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].[F:31][CH:32]([F:64])[O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[N:38]=[C:37]2[C:44]1[N:45]=[C:46]2[C:52]([C:53](O)=[O:54])=[CH:51][N:50]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:47]2=[N:48][CH:49]=1>CN(C=O)C>[F:64][CH:32]([F:31])[O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[N:38]=[C:37]2[C:44]1[N:45]=[C:46]2[C:52]([C:53]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:54])=[CH:51][N:50]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:62])([CH3:61])[CH3:63])[C:47]2=[N:48][CH:49]=1
Reactant: CC(C)(N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and 2-amino-2-methylpropan-1-ol (21.8 mg, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution. The reaction mixture stirred at 25° C. overnight. TLC and LCMS showed incomplete reaction added 2-amino-2-methylpropan-1-ol (21.8 mg, 245 μmol) and HATU (28.0 mg, 73.5 μmol) and the reaction continued at 25° C. for 3 h. Solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34.4 mg, 61.3 μmol, 100%) as an off-white solid. 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.43-7.52 (m, 1H), 7.34 (dd, J=8.9, 2.1 Hz, 1H), 6.53 (t, J=75.0 Hz, 1H), 5.72 (s, 2H), 4.21 (s, 3H), 3.79 (s, 2H), 3.53-3.64 (m, 2H), 1.55 (s, 6H), 0.85-1.07 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:14]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[O:13][C:8]([OH:12])([C:9](=[O:11])[OH:10])[CH2:7][C@@H:6]1[OH:21])(=[O:3])[CH3:2].C([O-])(O)=O.[Na+:26]>O>[Na+:26].[C:1]([NH:4][C@H:5]1[C@H:14]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[O:13][C:8]([OH:12])([C:9](=[O:10])[O-:11])[CH2:7][C@@H:6]1[OH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)[O-])C[C@@H]1O
Yield: 102.6 %

Procedure:
N-acetylneuraminic acid (1 g, 3.23 mmol) was dissolved in water (20 ml), then stirred with NaHCO3 (0.26 g, 3.09 mmol to PH 6˜6.5), after freeze-dried to afford the title product as white powder (1.05 g, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:11]=[C:12]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:13]=[C:7]2[OH:9])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(CC#N)c(C(=O)O)cc1Br
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1Br

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-2-cyanomethyl-4-methoxy-benzoic acid, 3-amino-5-methylpyrazol and acetic acid to give 7-Bromo-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 349 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:13])[C:7]=1[C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1.CC(C[AlH]CC(C)C)C.[BH4-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CCOCC.CO>[F:13][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]1([CH2:11][NH2:12])[CH2:10][CH2:9]1
Reactant: N#CC1(c2c(F)cncc2F)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: NCC1(c2c(F)cncc2F)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
1-(3,5-Difluoro-4-pyridyl)cyclopropanecarbonitrile (3.74 g, 20.8 mmol) was dissolved in Toluene (69.2 mL). At −10° C. DIBAL-H in Toluene 1.0M (43.6 mL, 43.6 mmol) was added dropwise to the yellow solution. The reaction mixture was stirred 30 min at −10° C. The mixture was then cooled down to −65° C. At −65° C. NaBH4 (4.81 g, 125 mmol) was added, then carefully 50 mL MeOH. The reaction mixture was stirred 1 h at −50° C., after approximately 30 min a sudden and strong gas evolution occurred and the temperature rose to −30° C. The reaction mixture was poured into 200 mL of 1M potassium sodium tartrate. The pale yellow solution was extracted 3 times with Ether. The combined organic phases were washed with brine and dried with Na2SO4, filtrated and the filtrate evaporated that gave a colorless mixture of oil and solid (3.95 g). The residue was dissolved in Ether and extracted with 4N HCl. The water layer was put to pH=10 with NaOH 30% in water until a white suspension appeared. The suspension was filtrated and washed with ether. The water layer from the filtrate was extracted 3 times with ether. The combined organic layers were dried with Na2SO4, filtrated and evaporated. The residue was a colorless mixture of oil and solid. The mixture was triturated with Ether and the solid was filtrated, the filtrate evaporated which gave the desired product as colorless oil (1.383 g).
Reaction SMILES: O=[C:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:21]([SH:24])[CH2:22][SH:23].O>ClCCl>[CH2:14]([C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:24][CH2:21][CH2:22][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC(=O)CCCCCCCC(=O)OC
Reactant: SCCS
Solvent: ClCCl
Solvent: O
Product: CCCCCCCC1(CCCCCCCC(=O)OC)SCCS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, methyl 9-oxo-hexadecanoate (No. 4984860; 2.39 g, 8.40 mmol) was dissolved in dichloromethane (47 mL), and the solution was cooled to 0° C. While maintaining the temperature at 0° C., 1,2-ethanedithiol (840 μL, 10.1 mmol), and borontrifluoride-ethylether complex (1.24 mL, 10.1 mmol) were sequentially added, and the mixture was stirred at 0° C. for 5 minutes and at room temperature for 2 hours. Water was added to the reaction solution to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was sequentially washed with a saturated sodium bicarbonate aqueous solution and a saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (SiO2 cartridge, 5.0% ethyl acetate/n-hexane, Rf=0.5) to obtain methyl 8-(2-heptyl-[1,3]dithiolan-2-yl)-octanoate (No. 5553355; 2.57 g, 85% yield).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]2[NH:31][C:30]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=3[N:28]=2)[CH3:26])=[O:23])=[CH:20][C:19]=1[Cl:39])=[O:17])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[NH2:8][CH2:9][CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]2[NH:31][C:30]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=3[N:28]=2)[CH3:26])=[O:23])=[CH:20][C:19]=1[Cl:39])=[O:17]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CCNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from 4-[(2R)-2-(tert-butoxycarbonylamino)ethylpyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.18 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C23H25Cl2N5O2 (474.39); mass spectrum: (M+H)+=474/476 (chlorine isotope) and (M−H)−=472/474 (chlorine isotope).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([NH:17][C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1]1)=[O:13])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: O=C(O)C1CCc2ccccc2O1
Product: C=CCNC(=O)C1CCc2ccccc2O1

Procedure:
3 Was prepared as white crystals, mp: 76°-77° C. from the ethyl ester of chroman-2-carboxylic acid (Witiak et al. (1971)) and 2-propenamine, by the procedure described in the last paragraph of Example 2.