Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1N.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl>CN(C)C=O.O>[CH2:9]([N:6]1[CH:7]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]2[CH:35]=[CH:34][C:33]([S:30](=[O:31])(=[O:32])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[CH:38][CH:37]=2)[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Reactant: O=C(O)Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1cc(NC(=O)Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid (29.2 mg, 0.1 mmol) in dry N,N-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (61 mL, 0.35 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (37.9 mg, 0.1 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water and acidified to pH=5.0 with a 0.01M aqueous hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-[1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[4-(pyridin-2-ylsulfamoyl)-phenyl]-acetamide (86%); 1H NMR(CDCl3, 300 MHz) δH 8.20–6.65 (m, 13H), 5.21 (broad s, 2H), 5.02 (s, 2H), 3.79 (t, J=7 Hz, 2H), 3.60 (s, 2H), 1.65–1.20 (m, 4H), 0.85 (t, J=7 Hz, 3H); LRMS for C28H29FN6O5S (M+H)+ at m/z=581.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1F)[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][O:14][CH2:15][CH2:16][OH:17].[H-].[Na+].Cl>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:17][CH2:16][CH2:15][O:14][CH3:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: COCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1ccc(C(=O)O)cc1C#N
Temperature: 70 °C
Yield: 93.2 %

Procedure:
3-Cyano-4-fluorobenzoic acid (500 mg, 3.03 mmol), 2-methoxyethanol (461 mg, 6.06 mmol), and 60% w/w NaH (363 mg, 9.08 mmol) were combined in acetonitrile (15 mL) and the reaction mixture was heated at 70° C. overnight. The reaction mixture was made acidic by the addition of 1N HCl and was extracted with ethyl acetate. The organics were dried over sodium sulfate, evaporated and purified by column chromatography (0-10% methanol in dichloromethane) to yield 3-cyano-4-(2-methoxyethoxy)benzoic acid (625 mg, 93%). 1H NMR (400 MHz, CD3CN) δ 9.60 (s, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 4.34 (dd, J=5.2, 3.7 Hz, 2H), 3.79 (dd, J=5.2, 3.6 Hz, 2H), 3.41 (s, 3H). The following compound was synthesized using the procedures described above: 3-cyano-4-propoxybenzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:4])=[O:5]
Reactant: COc1cc(C=O)ccc1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of OBS02011 (5.5 g, 21.21 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.88 g, 23.33 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave OBS02014 as a pale yellow oil (5.12 g, 92%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.18; 1H-NMR (270 MHz, CDCl3)=2.44 (1H, bs, OH), 2.92 (6H, s), 3.84 (3H, s), 4.60 (2H, s), 6.85 (1H, dd, J=2.2, 8.4), 6.97 (1H, d, J=1.8), 7.25 (1H, d, J=8.1).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=O>ClCCl>[CH2:12]([O:11][C:7](=[O:10])[CH:8]=[N:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[CH3:13]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)C=O
Solvent: ClCCl
Product: CCOC(=O)C=NC(C)(C)CO
Reaction time: 16 h
Yield: 98.1 %

Procedure:
2-Amino-2-methyl-1-propanol (9.54 ml, 0.10 mol) was added to a stirred solution of ethyl glyoxylate (50% soln. in toluene, 21 ml, 0.10 mol) in dichloromethane (100 ml) in the presence of 4Å molecular sieves. The reaction was stirred under nitrogen for 16 h whereupon the system was filtered through Dicalite® and washed with more dichloromethane. Evaporation of the solvent in vacuo gave (1,1-dimethyl-2-hydroxy-ethylimino)-acetic acid ethyl ester (17.0 g) as an oil (EIMS: m/z=174 [M+H]+). 2-Fluorobenzoyl chloride (0.60 ml, 5.00 mmol) and then pyridine (0.96 ml, 12.0 mmol) were added to a stirred solution of the above described ethyl ester (0.87 g, 5.00 mmol) in dichloromethane (8 ml) cooled to ˜5° C. and under nitrogen. After 1.5 h water (20 ml) was added, the layers separated and the aqueous phase washed with more dichloromethane (30 ml). The combined organic phase was then washed with 1N hydrochloric acid (25 ml) before being dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was purified by chromatography on silica using dichloromethane as eluant, to give 3-(2-fluorobenzoyl)4,4-dimethyl-oxazolidine-2-carboxylic acid ethyl ester (0.64 g) as an oil, EIMS: m/z=296 [M+H]+
Reaction SMILES: C#C.[NH:3]([CH2:7][CH2:8][CH2:9][CH:10]([NH:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[C:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=1)(=[O:25])=[O:24])=[O:16])[C:11]([OH:13])=[O:12])[C:4]([NH2:6])=[NH:5].[H][H]>O1CCCC1.O.[Pd]>[NH:3]([CH2:7][CH2:8][CH2:9][C@H:10]([NH:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=1)(=[O:25])=[O:24])=[O:16])[C:11]([OH:13])=[O:12])[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)NCCCC(NC(=O)c1sccc1NS(=O)(=O)c1cccc(C#Cc2cccnc2)c1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: C#C
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)c1sccc1NS(=O)(=O)c1cccc(CCc2cccnc2)c1)C(=O)O

Procedure:
The acetylene (EG00298/5-Guanidino-2-{[3-(3-pyridin-3-ylethynyl-benzenesulfonyl amino)-thiophene-2-carbonyl]amino}-pentanoic acid; approx 10 mg) was dissolved in tetrahydrofuran:water (4:1, 2 mL), palladium on charcoal (approx 10% weight) was added and a hydrogen atmosphere introduced by balloon. The reaction mixture was stirred at 20° C. for 24 hours with occasional refilling of the hydrogen balloon. After this time the reaction mixture was filtered over Celite™ and the solvent removed in vacuo. The yellow residue was purified using preparative LCMS.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24]C1C(=O)C=COC=1C)C1C=CC=CC=1.C(N1C=CC(=O)C(O)=C1C)(=O)C.[NH2:45][CH2:46][C:47]([OH:49])=[O:48].OCCN>>[CH2:1]([O:8][C:9]1([OH:24])[C:14](=[O:15])[CH:13]=[CH:12][N:45]([CH2:46][C:47]([OH:49])=[O:48])[CH:10]1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: CC(=O)n1ccc(=O)c(O)c1C
Solvent: NCCO
Product: CC1N(CC(=O)O)C=CC(=O)C1(O)OCc1ccccc1

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with glycine under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one, which is deprotected using the procedure described under (I) to give 1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one as white crystals, m.p. >230° C.; δmax (nujol) 1625, 1645 cm-1 ; δ(d6DMSO) 1.9 (s, 3H), 4.3 (s. 2H), 5.9 (d, 1H), 7.35 (d, 1H).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=O)[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(=O)C.[NH4+].[BH3-]C#[N:28].[Na+]>>[NH2:28][CH:13]1[CH2:14][C:15]([CH3:17])([CH3:16])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:20])([CH3:19])[CH2:12]1
Reactant: CCCCCCCCON1C(C)(C)CC(=O)CC1(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Yield: 61.5 %

Procedure:
4-Amino-N-octyloxy-2,2,6,6-tetramethylpiperidine (16.7 g, 62%) is prepared from N-octyloxy-4-oxo-2,2,6,6-tetramethylpiperidine (95.4 mmol, 27.0 g) by the same method as described above, with the exception of the addition of ammonium acetate (954.5 mmol, 73.5 g), 15 g molecular sieves (10−10 m) and 95% NaBH3CN (95.4 mmol, 6.32 g). 1H-NMR (CDCl3); δ=3.61 (t, J=6.6 Hz, 2H, CH2—O), 2.99 (m, 1H, NH2—CH), 1.63 (d, J=11.4 Hz, 2H, NH2), 1.46 (m, 4H, CH2—CH3), 1.26 (m, 12H), 1.15 (s, 6H, CH3), 1.12 (s, 6H, CH3), 0.87 (t, J=7.4 Hz, 3H, CH2—CH3); 13C-NMR (CDCl3): δ=77.0, 59.8, 50.1, 41.4, 33.2, 31.8, 29.6, 29.2, 28.6, 26.4, 21.3, 21.4, 14.1.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(OCC)(=O)C.CC1(C)N([O])C(C)(C)CCC1>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Yield: 101.9 %

Procedure:
4.7 g (38.4 mmol) of rac.-1-phenylethanol and 3.18 g (40.2 mmol) of pyridine were dissolved in 60 ml of ethyl acetate under an inert gas in a 200 ml sulphonation flask. The mixture was cooled to 0° C. while stirring and treated with 60 mg (0.28 mmol) of TEMPO derivative E. Thereafter, a solution of 3.6 g (15.5 mmol) of trichloroisocyanuric acid in 38 ml of ethyl acetate was dosed in within 1 hour at a temperature of 0°-3° C. The reaction mixture was stirred at 0°-3° C. for a further 1 hour. Thereafter, the reaction had finished. The white precipitate was filtered off and the filtrate was treated with a solution of sodium pyrosulphite in order to reduce the excess trichloroisocyanuric acid. The filtrate was washed with sodium bicarbonate solution and with sodium chloride solution. 4.7 g (102%) of acetophenone were obtained as the crude product, GC content: 99.8%. Distillation of the crude product gave 3.19 g (69%) of acetophenone, GC content: 99.9% (area percent).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH:17]2[CH:13]1[CH2:14][N:15]([C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][N:19]=1)[CH2:16]2.O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH:13]2[CH:17]1[CH2:16][N:15]([C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)[CH2:14]2
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3Nc2ccc3ccccc3n2)nc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CC3C(C2)C3Nc2ccc3ccccc3n2)nc1
Yield: 30.3 %

Procedure:
Ethyl 2-[6-(quinolin-2-ylamino)-3-azabicyclo[3.1.0]hex-3-yl]pyrimidine-5-carboxylate (0.98 mmol) was stirred in THF (10 ml) and H2O (10 ml) at r.t. for 64 h. The reaction was then acidified to pH˜3 and the solvent removed in vacuo to give a brown solid. The solid was collected and washed with a little H2O to give the title compound as a brown solid (103 mg, 30% over 3 steps). LCMS purity 90%, m/z 348 [M+H]+.
Reaction SMILES: NC[C:3]1[C:8]([CH2:9][NH:10][C:11]2[NH:12][C:13](=[O:20])[C:14]3[NH:15][CH:16]=[N:17][C:18]=3[N:19]=2)=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(C)=O.C(#N)C.C([O-])(=O)C.C([NH+](CC)CC)C>O>[CH2:9]([NH:10][C:11]1[NH:12][C:13](=[O:20])[C:14]2[NH:15][CH:16]=[N:17][C:18]=2[N:19]=1)[C:8]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1CNc1nc2nc[nH]c2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: CC[NH+](CC)CC
Solvent: O
Solvent: CS(C)=O
Solvent: CC#N
Product: O=c1[nH]c(NCc2ccccc2)nc2nc[nH]c12
Reaction time: 1 h

Procedure:
Introduced into a 1.5 ml Eppendorf tube were 100 μl of a solution containing 10 mmol·l−1 of 6-aminomethylbenzylguanine in anhydrous dimethylsulfoxide (1 μmol) and 100 μl of a solution containing 10 mmol·l−1 of Tb(KR)-NHS in anhydrous dimethylsulfoxide (1 μmol). The mixture was stirred for one hour. The reaction was monitored by HPLC on a Merck Lichrospher RP °18, 5 μm, 125×4.6 column with a gradient of acetonitrile in water containing 25 mM of triethylammonium acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:14]=2[N:15]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:22]3[O:21][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH:23]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)ccc3o2)c1
Reactant: OB(O)c1cc2ccccc2o1
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4cc5ccccc5o4)ccc3o2)c1

Procedure:
Prepared by the method of Example 15d), from 2-(2-fluoro-5-nitrophenyl)-5-bromobenzoxazole (1.00 g, 3.0 mmol) and benzofuran-2-boronic acid (728 mg, 4.50 mmol) the subtitle compound was obtained (208 mg, 18%). The product was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OO
Reactant: Fc1ccccc1Oc1cccnc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2ccccc2F)c1
Reaction time: 16 h

Procedure:
A solution of 30 g of 3-(o-fluorophenoxy)pyridine in 50 ml of glacial acetic acid is treated at 35° C. with 33 g of 40% peracetic acid in acetic acid in four portions. The mixture is stirred for 16 hours, refluxed 1 hour and 50 ml of isopropanol is added and the heating continued at 95° C. for 1 hour. The mixture is concentrated at reduced pressure and is dissolved in 300 ml of dichloromethane. The solution is washed with excess 25% sodium hydroxide solution. The dichloromethane solution is dryed over anhydrous MgSO4, filtered and concentrated at reduced pressure. The 3-(o-fluorophenoxy)-pyridine N-oxide crystallizes, mp 89°-95° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:4].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.C(OC(C)C)(C)C>[C:19]([O:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:4])(=[O:21])[CH3:20]
Reactant: NC(=NO)c1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON=C(N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the product obtained in Step A above (8.43 g, 32.17 mmol) in 200 ml of CH2Cl2 there are added 6.72 ml (48.2 mmol) of triethylamine. 3.34 ml (35.4 mmol) of acetic anhydride are added dropwise and the solution is stirred overnight at ambient temperature. After washing 3 times with water and then with brine, the organic phase is dried over MgSO4 and evaporated. The solid obtained is taken up in isopropyl ether and then filtered to yield the title product.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:17][CH:18]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1ccc(Br)nc1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(Cl)cn1
Yield: 80 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-5-chloropyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 118 mg, 80%) which was obtained as a light yellow solid. MS: m/e=297.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=[C:12](I)[C:5]=12)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[N:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=[C:12]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[N:35]=3)[C:5]=12)[CH3:2]
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Reactant: CCOc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ncnc2c1c(-c1cccc(F)n1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
4-ethoxy-3-iodo-1-trityl-pyrazolo[3,4-d]pyrimidine (590 mg, 1.11 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (296.7 mg, 1.33 mmol) and Na2CO3 (1.662 mL of 2 M, 3.324 mmol) were suspended in anhydrous Dioxane (25 mL) and degassed (vacuum/nitrogen cycles×5). Pd[P(tBu)3]2 (56.62 mg, 0.11 mmol) was added and the reaction mixture was degassed again (vacuum/nitrogen cycles×5) and stirred at 60° C. for 3 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. DCM, saturated aqueous Na2CO3 and brine were added and the aqueous layer was extracted with DCM (4×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 120 g column, eluting with EtOAc/petroleum ether) to give the sub title compound (139.1 mg, 25% Yield). 1H NMR (400 MHz, DMSO) δ 8.17 (1H, s), 7.77 (1H, m), 7.63 (1H, m), 7.24-7.11 (15H, m), 6.89-6.81 (1H, m), 4.50 (2H, q) and 1.44 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:22])=[CH:13]1.C([O-])([O-])=O.[K+].[K+].[CH3:29][N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:29][NH:30][C:31](=[O:32])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[C:14]2[CH3:22]
Reactant: CN=C=O
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(c1)c(C)cn2NCCCc1ccncc1F
Reaction time: 15 h

Procedure:
To a solution consisting of 1-[(3-fluoro-4-pyridinyl)propylamino]-3-methyl-1H-indol-5-ol (2.10 g) and tetrahydrofuran (47 ml) was added milled K2CO3 (1.02 g) followed by dropwise addition of methyl isocyanate (0.46 ml) at room temperature under nitrogen. Stirring was continued for 15 hours, at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, 50% EtOAc/dichloromethane) afforded 2.35 g of the desired carbamate as a solid. The product was recrystallized from ether, m.p. 163°-164° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: CC(=O)Nc1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(C=O)c1
Yield: 93 %

Procedure:
A mixture of N-[3-(hydroxymethyl)phenyl]acetamide (10 g, 60.6 mmol) and MnO2 (7.8 g, 90 mmol) in toluene (250 mL) was refluxed for 29 hr, with addition of more MnO2 (0.7 g, 9 mmol) at 24 hr. The reaction was cooled, filtered through Celite and concentrated in vacuo to give N-(3-formylphenyl)acetamide (9.2 g, 75%). ES-MS (M+H)+=164.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:7][C:8]=1[C:9](=[N:11][OH:12])[CH3:10].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23](S(C)(=O)=O)[N:22]=1>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:7][C:8]=1[C:9](=[N:11][O:12][C:23]1[N:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:21]([O:20][CH3:19])[N:22]=1)[CH3:10]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC(=NO)c1sc(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(ON=C(C)c2sc(-c3cccnc3)nc2Cl)n1
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (NaH, 60% dispersion in mineral oil: 48 mg, 1.2 mmol) in DMF (2 ml) was added a solution of 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone oxime (253.7 mg, 1 mmol) in DMF (3 ml), and the resulting frothy mixture was stirred for 1 hour. After that, 4,6-dimethoxy-2-methylsulfonyl-pyrimidine (218 mg, 1 mmol) was added into the above solution. The homogeneous, dark-red solution was stirred at ambient temperature for 18 hours. The precipitated brown solid was filtered and washed with water and dried under vacuum to afford the brown solid of 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]-N-(4,6-dimethoxypyrimidin-2-yl)oxy-ethanimine in a mixture of Z and E-isomers. 1H NMR (300 Mz, CDCl3): δ: 9.16 (s, 1H), 8.70 (d, 1H, J=4.8 Hz), 8.24 (m, 1H), 7.41 (m, 1H), 5.84 (m, 1H), 3.97 (m, 6H), 2.79 (m, 2H). MS (ESI): 392 (M+1), 414 (M+Na).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[Si:12]([O:19][C@H:20]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])/[CH:21]=[N:22]/[S@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CCOCC>[Si:12]([O:19][C@H:20]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[C@@H:21]([NH:22][S@:23]([C:25]([CH3:26])([CH3:27])[CH3:28])=[O:24])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: Brc1nccs1
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@@H](c1nccs1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 2-bromothiazole (7.9 ml, 89 mmol) in 200 mL ether was cooled to −78° C. and treated with a solution of n-butyllithium (36 ml, 89 mmol) (2.5N in hexanes). After stirring for 30 minutes the reaction mixture was slowly added to a cooled (−78° C.) suspension of (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (25.000 g, 59 mmol) in 100 mL ether. The reaction mixture was allowed to stir at −78° C. for one hour. The reaction mixture was quenched with MeOH and saturated NH4Cl solution. The organic solution was washed with water, brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography gave (S)—N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (24.81 g, 83% yield).