Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].CC1C=CC=C(C)C=1N.O1C(C)C1.[OH-].[Na+]>C1C=CC=CC=1.O>[Cl:3][CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1NCC(C)O
Agent: CC1CO1
Agent: Cc1cccc(C)c1N
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C)c1NCC(C)Cl
Reaction time: 5 h
Yield: 77 %

Procedure:
A solution of 123 ml (202 g, 1.7 moles) of thionyl chloride in 200 ml of dry benzene is added dropwise to a solution of 100 g (0.558 moles) of N-(β-hydroxypropyl)-2,6-dimethyl-aniline (prepared from 2,6-dimethylaniline and 1,2-epoxipropane as described in the published Dutch patent application No. 6,507,312; b.p.: 120°-125° C./1 mm Hg; yield: 51%) in 1000 ml of dry benzene at room temperature under nitrogen atmosphere. The resulting mixture is stirred and boiled under nitrogen atmosphere for 5 hours. The mixture is cooled with icy water, 100 ml of water are added dropwise to the cooled mixture, and the pH of the resulting mixture is adjusted to 9 with 10 n aqueous sodium hydroxide solution. The phases are separated from each other, and the aqueous phase is extracted thrice with 200 ml of benzene each. The organic solutions are combined, washed thrice with 300 ml of water each, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residual dark brown oil is divided into two parts of about equal weights, and then distilled under reduced pressure. 85 g (77%) of N-(β-chloropropyl)-2,6-dimethyl-aniline are obtained as a colourless oil boiling at 105°-108° C./0.8 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C@@H:8]([O:11]C(=O)C2C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=2)[C:9]#[CH:10])=[CH:4][CH:3]=1.CO.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#C[C@@H](COc1ccc(F)cc1)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#C[C@H](O)COc1ccc(F)cc1
Reaction time: 3.5 h
Yield: 80.8 %

Procedure:
To a solution of (3S)-4-(4-fluorophenoxy)-3-(3′,5′-dinitrobenzoyl)oxy-1-butyne (10.35 g, 98% ee, 27.6 mmol) in THF (115 mL), was added methanol (115 mL) and K2CO3 (0.58 g). After stirring for 3.5 hours, the reaction mixture was quenched with acetic acid (2 mL). The solvents were evaporated and the resulting slurry was filtered and the solid was washed with ether. The filtrate was concentrated and the filtration/ether wash sequence was repeated. Concentration gave 4.02 g of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (98% ee), a compound of formula (BB); 1H NMR (CDCl3) δ 2.56 (s, 1H), 4.10 (m, 2H), 4.78 (m, 1H), 6.85 (m, 2H), 7.0 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[Cl:28][C:29]1[N:34]=[C:33]([CH3:35])[C:32]([NH2:36])=[CH:31][CH:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=C(P(C(C)(C)C)C(C)(C)C)C=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:36][C:32]3[C:33]([CH3:35])=[N:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1N
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1cccc(-c2ccccc2)c1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1nc(Cl)ccc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Temperature: 120 °C
Yield: 30.9 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.546 g, 4.93 mmol), palladium acetate (110 mg, 0.49 mmol), biphenyl-3-yl-di-tert-butyl-phosphane (18.5 mg, 0.062 mmol), sodium tert-butoxide (1.20 g, 12.5 mmol), and 6-chloro-2-methyl-pyridin-3-ylamine (709 mg, 4.97 mmol) in 15 mL dioxane was heated in microwave for 2 hour at 120° C. Solids were filtered off and mixture was purified to give Compound A90 as a tanned solid (640 mg, 31%). 1H NMR (CDCl3, 400 MHz) δ 1.11-1.12 (d, 6H), 1.52-1.62 (m, 2H), 1.81-1.89 (m, 2H), 1.98 (s, 3H), 2.23 (m, 3H), 3.21-3.30 (m, 2H), 3.59-3.70 (m, 3H), 5.14-5.17 (m, 1H), 6.83-6.91 (m, 1H), 7.14-7.16 (d, 1H), 7.55-7.57 (d, 1H), 7.87 (s, 1H). Exact mass calculated for C20H26ClN5O3 419.17, found 419.9 (MH+).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].C(OC([N:32]1[C:40]2[C:35](=[CH:36][C:37]([P:41]([O:45]C)([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=2)[C:34](I)=[N:33]1)=O)(C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH3:44][O:43][P:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][N:33]=[C:34]2[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:42])[OH:45]
Reactant: COP(=O)(OC)c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(O)c1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 43.7 %

Procedure:
82.9 mg (0.25 eq; 0.072 mmol) of tetrakis(triphenylphosphine)palladium(0), 150.1 mg (2 eq; 0.575 mmol) of 1-boc-indole-2-boronic acid, 5 ml of dimethylformamide and 250 μl of saturated sodium bicarbonate solution are added to 130 mg (1 eq; 0.287 mmol) of 5-(dimethoxyphosphoryl)-3-iodo-indazole-1-carboxylic acid tert-butyl ester. The medium is stirred at 130° C. for 5 hours. The reaction medium is filtered through paper and the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 41 mg of [3-(1H-indol-2-yl)-1H-indazol-5-yl]-phosphonic acid monomethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH:8]=[CH:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3][C:4](=[O:7])[CH2:5][CH3:6].[OH-].[K+].[BH4-].[Na+].[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][CH2:12][CH:11]([CH3:18])[CH2:10][CH:9]=[CH:8][C:2]([CH3:1])=[CH:3][C:4](=[O:7])[CH2:5][CH3:6])[CH3:24]
Reactant: CCC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Reactant: CCO
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)CC
Reaction time: 2 h

Procedure:
To a solution of 2 g. of 5,9,13-trimethyltetradeca-4,6,12-trien-3-one in 20 ml. of ethanol, cooled to 0° by an ice-bath, is added a suspension of 2.32 g. of mercuric acetate in 50 ml. of ethanol over 15 minutes. The reaction mixture is stirred for 2 hours and then with cooling, to -20°, 1.22 g. of potassium hydroxide in 20 ml. of ethanol is added. Then 0.139 g. of sodium borohydride is added in small portions and stirring continued for 30 minutes at -20°. The solution is decanted, then concentrated to half volume, diluted with 100 ml. of water and extracted with ether (3 × 50). The ethereal phase is washed with water, dried over magnesium sulfate and the crude product chromatographed on silica to yield 13-ethoxy-5,9,13-trimethyltetradeca-4,6-dien-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: COc1ccccc1-c1ccc(C=O)cc1
Product: COc1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-Methoxy[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[C:23]([F:25])([F:26])[F:24])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)Nc6ccncc6C(F)(F)F)CC5)C4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)Nc3ccncc3C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 20 mL vial was charged with 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide (56 mg, 0.1 mmol), trifluoroacetic acid (1.5 mL, 19 mmol) and methylene chloride (1.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated in vacuum. The residue was dissolved in 3 mL of a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, HPLC purification (method B) gave the title compound 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide. LC-MS: 551.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[N:29]=[C:30](Br)[S:31][C:32]=2[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:50]2[N:55]=[C:54]([OH:56])[CH:53]=[CH:52][CH:51]=2)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[N:29]=[C:30]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]([OH:56])[N:55]=3)[S:31][C:32]=2[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: CC1(C)OB(c2cccc(O)n2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(O)n3)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](NC(=O)OCc2ccccc2)CC1

Procedure:
In a microwave reaction vial, tert-butyl N-[4-[[5-[(4S)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-bromo-thiazol-5-yl]carbamate (200 mg, 0.31 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (205 mg, 0.93 mmol) and PDCL2(DPPF) (23 mg, 0.031 mmol) were dissolved in acetonitrile (8 mL). Potassium acetate (1.0M, 0.46 mL, 0.46 mmol) was sodium carbonate (1.0M, 0.46 mL, 0.46 mmol) were added and the mixture was irradiated with a microwave for 30 min at 120° C. The mixture was cooled, filtered through Na2SO4 and Celite, concentrated and purified via flash chromatography, methanol/DCM 0% to 10% to afford tert-butyl N-[4-[[5-[(4S)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(6-hydroxy-2-pyridyl)thiazol-5-yl]carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.Cl(O)(=O)(=O)=O.[H][H].C([O-])(=O)C.[K+]>[Pd].C(O)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2
Reactant: COc1ccc(OC)c2c1CCC2=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(OC)c2c1CCC2
Yield: 48.2 %

Procedure:
A mixture of intermediate A (19 g, 99 mmole), perchloric acid (2.5 ml of a 70% aqueous solution) and 10% palladium on carbon catalyst (2 g) in acetic acid (250 ml) was placed in a Paar bottle and shaken under 40 psi (2.75 bars) of hydrogen in a Paar shaker apparatus for 15 hours. Solid potassium acetate was added, and the mixture was filtered through a Celite pad. The Celite pad was washed with tetrahydrofuran, and the combined filtrates were poured into ice water (2 liters). The resulting white solid was isolated by filtration, washed with water, and dried under vacuum. Chromatography (silica, dichloromethane) afforded the desired product, 4,7-dimethoxyindane (intermediate B) as a white solid (8.5 g). White needles were obtained from ethanol:water (1:1), mp 82°-84°.
Reaction SMILES: [CH2:1]([N:6]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]([C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18](O)=[O:19])[CH:17]=[C:11]2[CH:10]=1)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:6]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]([C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:19])[CH:17]=[C:11]2[CH:10]=1)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(C(=O)O)cc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(C(=O)N3CCOCC3)cc2c1
Yield: 74.7 %

Procedure:
5-(diisopentylcarbamoyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid (0.29 g, 0.840 mmol), EDC (0.274 g, 1.427 mmol) and HOBT (0.219 g, 1.427 mmol) were combined in DMF (2.0 ml). Added triethylamine (0.351 ml, 2.52 mmol) and morpholine (0.073 ml, 0.840 mmol) and stirred at 22° C. for 12 h. The mixture was diluted with ethyl acetate (25 ml) and washed with water, saturated sodium bicarbonate solution and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography: ISCO Gold 24 g using 0% to 100% ethyl acetate in hexanes over 11 min. Pooled and concentrated desired fractions to afford, 0.26 g (74%) of the title compound as a clear oil. LCMS m/z 415.3 (M+H)+. ret. time=2.27 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])(=[O:9])[CH:7]=[CH2:8]>>[OH:14][CH:12]([CH3:13])[CH2:11][O:10][C:6](=[O:9])[CH2:7][CH2:8][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)OCC(C)O
Product: CC(O)COC(=O)CCn1ccnc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, in a three-necked flask provided with a mechanical stirrer, at room temperature, 20.43 g imidazole (0.30 mol) are suspended in 39.06 g 2-hydroxypropyl acrylate (0.30 mol). The contents of the flask are heated to 40° C., until an exothermic reaction occurs, whereby the temperature rises to about 110° C. within a few minutes. The reaction mixture is cooled to 80° C. and then stirred at this temperature for 3 h. The clear yellow oil (amine value 271 mgKOH/g; color 4 (Gardner)) is quantitatively filtered off and stored dry.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][C:13]([CH3:18])([CH3:16])[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC(COCc2ccccc2)OC1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 2,2-dimethyl-1,3-propanediol (4.16 g, 40 mmol) and toluene (70 ml), p-toluenesulfonic acid monohydrate (287 mg, 1.51 mmol) was added and refluxed for 4 hours while removing water by the Dean-Stark apparatus. After the reaction mixture was cooled to room temperature, triethylamine (4 ml) was added to the reaction mixture and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/9) to obtain the title compound (7.6 g, yield: 96.6%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(F)nc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=309.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-5-methyl-pyridine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=[O:21])[CH2:15][CH2:14]1
Reactant: CON1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CON1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (23.8 g, 189 mmol) in 100 ml of methylene chloride, DMSO (29.6 g, 380 mmol) was added slowly and the mixture was stirred for 0.5 h at the same temperature. Then, a solution of 2-(1-methoxy-piperidin-4-yl)-ethanol (12 g, 75 mmol) in 50 ml of methylene chloride was added. After stirring for 30 minutes, triethylamine (44 g, 430 mmol) was added to the mixture. After the addition, the reaction mixture was warmed to room temperature and diluted with methylene chloride. The organic solution was washed with water and aqueous NaHCO3. The organic layers was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel. Yield: 11.5 g of (1-methoxy-piperidin-4-yl)-acetaldehyde as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:22]([NH:24][CH:25]2[CH:29]([O:30]CC3C=CC=CC=3)[O:28][C:27](=[O:38])[CH2:26]2)=[O:23])[CH3:21])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:22]([NH:24][CH:25]([CH:29]=[O:30])[CH2:26][C:27]([OH:38])=[O:28])=[O:23])[CH3:21])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)CCc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)CCc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)NC(C=O)CC(=O)O
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of 195 mg of N-(3-(4-hydroxyphenyl)propionyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran in 5 mL of methanol was added ~100 mg of Pd(OH)2 on carbon. After the mixture had been stirred vigorously under hydrogen for 3 hours, the mixture was filtered through a 0.22 μm nylon membrane filter and concentrated. The residue was purified by MPLC on silica-gel (22×300 mm column, eluted with a gradient of dichloromethane to 8% formic acid and 32% methanol in dichloromethane) to afford 115 mg of the title compound as a colorless solid: 1H NMR (400 MHz, CD3OD (1:1 mixture of diastereomeric hemiacetals in this solvent)) δ7.01 (d, 2H, J=8.39 Hz, Ar--H), 6.67 (d, 2H, J=8.53 Hz, Ar--H), 4.58 (d, 0.5H, J=3.92 Hz, CH(OH)(OCD3)), 4.56 (d, 0.5H, J=4.06 Hz, CH(OH)(OCD 3)), 4.34 (m, 1H, CHN), 4.24 (m, 1H, CHN), 4.09 (d, 1H, J=7.10 Hz, CHN), 2.81 (t, 2H, J=7.56 Hz, CH2CON), 2.7-2.4 (m, 4H, CH2Ar, CH2CO2), 2.00 (m, 1H, CH(CH3)2), 1.32 (d, 3H, J=5.81Hz, CHCH3), 0.89 (d, 3H, J=6.82 Hz, CH(CH3)2), 0.85 (d, 3H, J=6.87 Hz, CH(CH3)2).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:9]2[N:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11]([Cl:17])[N:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:9]2[N:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11]([Cl:17])[N:10]=2)[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(C(Cl)(c2ccccc2)c2ccccc2)nc(Cl)c1Cl
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Clc1nc(C(c2ccccc2)(c2ccccc2)n2ccnc2)nc(Cl)c1Cl

Procedure:
34.0 g (0.1 mol) of diphenyl-4,5,6-trichloropyrimid-2-yl-chloromethane in 250 ml of absolute acetonitrile are stirred with 13.6 g (0.2 mol) of imidazole for 3 hours at room temperature and thereafter heated to the boil for 15 minutes. The mixture is then concentrated and the dark brown residue is washed with water and taken up in methylene chloride. After drying with sodium sulphate, treating with active charcoal and filtering, the solution is concentrated. The residue is extracted by boiling with petroleum ether, and the mixture is filtered and again concentrated. Finally, the material is recrystallised from a little acetonitrile. 17.0 g (40% of theory) of the compound of formula ##SPC9##
Reaction SMILES: [I:1][C:2]1[C:3]([NH:17]C(=O)OC)=[CH:4][C:5]([NH:8][C:9]([CH3:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])=[N:6][CH:7]=1.[OH-].[K+].C(O)C>O>[I:1][C:2]1[C:3]([NH2:17])=[CH:4][C:5]([NH:8][C:9]([CH3:10])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:16])=[N:6][CH:7]=1
Reactant: COC(=O)Nc1cc(NC(C)(C)CC(C)(C)C)ncc1I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1cc(N)c(I)cn1
Temperature: 80 °C
Yield: 81 %

Procedure:
A mixture of methyl {5-iodo-2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}carbamate (1.3 g, 3.2 mmol), potassium hydroxide (898 mg, 16 mmol), ethanol (10 mL) and water (10 mL) was heated at 80° C. for 2 hours. Ethanol was removed under vacuum, and the residue was stirred in water. The precipitated solid was filtered under vacuum and dried to yield 900 mg (81%) of 5-iodo-N2-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.C1COCC1>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1ccccc1I
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -4 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-iodophenyl)methanol (5.88 g, 0.0251 mol) in tetrahydrofuran (40 mL, 0.5 mol) at −78 Celsius was added 1.600 M of n-butyllithium in hexane (31.7 mL). The mixture was stirred at −4 Celsius for 1 hour, then cooled to −78 Celsius. A solution of 1-benzylpyrrolidin-3-one (3.67 mL, 0.0228 mop in THF (2 mL) was added to the above mixture, and the resulting mixture was stirred at −78 Celsius for 2 hours. The reaction was quenched with small amount of brine, then extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel column with 70% AcOEt in hexanes to give the desired compound (3.5 g, 54% yield). MS (ESI): 284.1 (M+H+).