Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:4]2[CH:3]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:19]([O:18][C:16]([NH:17][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:4]2[CH:3]=1)=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCOC(=O)c1nc2cc(Br)ccn2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Temperature: 110 °C
Reaction time: 20 h
Yield: 53.6 %

Procedure:
To an argon purged solution of ethyl 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.76 g, 6.52 mmol) in dioxane (45 ml) are added tert-butyl carbamate (916 mg, 7.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (119 mg, 130 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (151 mg, 261 μmol) and cesium carbonate (2.97 g, 9.12 mmol). The resulting mixture is heated to 110° C. and stirred for 20 hours. The reaction mixture is loaded on silica and purified by flash chromatography on a 50 g silica column using heptane/ethyl acetate 30-100% as eluent affording ethyl 7-(tert-butoxycarbonylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.07 g, 54%) as a light yellow solid. mp.: 220-2° C. MS: m/z=307.3 (M+H+).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].[CH3:24][C:25](C)([O-])[CH3:26].[K+].IC(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:25]([CH3:26])[CH3:24])[CH:16]=1)=[O:14]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
A solution of eq-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (320 mg, 1.08 mmole) in dry THF (15 ml) at room temperature under nitrogen was treated with potassium t-butoxide (125 mg, 1.1 mmole) and stirred for 20 minutes. The solution was then treated with 2-iodopropane (0.11 ml, 1.1 mmole) and stirred for 18 h. The reaction mixture was treated with 10% Na2CO3 solution (25 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E18) as a colourless oil (240 mg, 63%). This was converted to the hydrochloride salt mp 235°-238° C. (acetone).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.CCO>[Pd].C(OCC)(=O)C>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)c(N)c1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 4-hydroxy-3-nitrobenzonitrile (100 mg, 0.61 mmol), palladium on charcoal (10 mg, 10%), EtOH (0.67 mL) and ethyl acetate (0.33 mL) was hydrogenated at rt for 2 h. Then the mixture was filtered and concentrated to give 3-amino-4-hydroxybenzonitrile 60 mg (73%) as a solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25](=[O:27])[CH2:24][C:23]2=[O:28])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:30]1(C)[CH:35]=CC(S(O)(=O)=O)=C[CH:31]=1>C(O)CC>[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][CH2:31][CH2:30][CH3:35])=[CH:24][C:23]2=[O:28])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(=O)CC2=O)n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCO
Product: CCCOC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 105.5 %

Procedure:
(S)-3-cyclohexyl-2-(2,4-dioxo-pyrrolidin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (100 mg, 0.26 mmol) was added to n-propyl alcohol (3 mL), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated and the crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(2-oxo-4-propoxy-2,5-dihydro-pyrrol-1-yl)-propionamide (24 mg, 22%) as an off-white solid: LR-ES-MS m/z calculated for C22H34N4O4 [M]+ 432, observed [M+H]+ 433; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.82-0.95 (m, 5H), 0.96-1.14 (m, 2H), 1.27 (d, J=6.0 Hz, 6H), 1.37-1.89 (m, 11H), 3.90 (d, J=17.6 Hz, 1H), 3.88 (s, 2H), 4.28 (d, J=17.6 Hz, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.67 (s, 1H), 4.76 (dd, J=10.3, 3.9 Hz, 1H), 5.12 (s, 1H), 6.42 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:22][CH3:23])[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=[O:15])=[CH:7][CH:6]=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:22][CH3:23])[C:14]([NH:16][C:17]([CH3:20])([CH3:21])[CH:18]=[O:19])=[O:15])=[CH:7][CH:6]=2
Reactant: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C)C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-(3-Bromo-quinolin-6-yloxy)-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methylsulfanyl-acetamide (0.2 g) from Stage 2, Step 1 above in dichloromethane (15 ml) was treated with Dess-Martin periodinane (0.42 g). The reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched with sat. aqueous NaHCO3 and sat. aqueous sodium thiosulphate. The reaction mixture was vigorously stirred at rt. for 30 minutes after which time the two phases were separated. The organic layer was washed with sat. aqueous. NaHCO3. After separation the organic phase was dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 1:1) to give 2-(3-bromo-quinolin-6-yloxy)-N-(1,1-dimethyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide as white solid (0.188 g). 1H NMR (CDCl3) δ ppm: 9.41 (1H, s); 8.83 (1H, d); 8.26 (1H, d); 8.08 (1H, d); 7.51 (1H, dd); 7.22 (1H, d); 5.69 (1H, s); 2.20 (3H, s); 1.53 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[S:16][C:10]=3[C:9]2=[O:25])=[CH:4][C:3]=1[O:26][CH3:27].Cl.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[H-].[Na+].Cl.CCOC(C)=O>CN(C=O)C.CO>[ClH:29].[CH3:27][O:26][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[S:16][C:10]=3[C:9]2=[O:25])[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(O)c(OC)c2)CC3)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OCCN4CCOCC4)c(OC)c2)CC3)cc1
Yield: 20 %

Procedure:
Treat 6-(4-hydroxy-3-methoxy-phenyl)-2-(4-methoxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (0.12 g, 0.31 mmol) in DMF (5 mL) with 4-(2-chloro-ethyl)-morpholine hydrochloride salt (59 mg, 0.31 mmol) and 60% NaH (38 mg, 0.94 mmol). Stir the reaction at 85° C. overnight. Quench with water (5 mL) and dilute with EtOAc (150 mL). Separate the phases and wash the organic phase with water (3×50 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 1% NH3—H2O, 10% CH3OH and 90% EtOAc to give 31 mg. Dissolve the material in CH3OH (2 mL), and treat with 1.0 M HCl in EtOAc (65 μL, 0.065 mmol), with stirring at RT for 5 min. Remove the solvent in vacuo to give 33 mg (20%) of the title compound. LC-MS/ES m/z 495.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.I[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1>>[OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:29])([F:28])[F:30])[NH:16][C:17]3=[O:20])=[CH:12][CH:11]=2)[C:5](=[O:8])[CH2:4]1
Reactant: O=C1CC(CO)CN1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Product: O=C1CC(CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1

Procedure:
4-Hydroxymethylpyrrolidin-2-one, which is a known compound described in a publication (Journal of Chemical Research, Synopses, vol. 9, pp. 430-431, (1996)) and the 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step D of Example 1-1 were used as raw materials. Using such raw materials, the captioned compound was synthesized by a reaction similar to step E of Example 1-1.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH3:39][O:40][C:41]1[CH:60]=[CH:59][C:44]([CH2:45][C@H:46]([CH2:50][C:51]([N:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:52])[C:47]([OH:49])=O)=[CH:43][CH:42]=1>>[CH2:26]([NH:25][C:23](=[O:24])[C@H:22]([CH3:30])[CH2:21][C@H:20]([OH:31])[C@@H:19]([NH:18][C:16](=[O:17])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:47](=[O:49])[C@H:46]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:60][CH:59]=1)[CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:52])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(C[C@H](CC(=O)N2CCCCC2)C(=O)O)cc1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCCCC1)Cc1ccc(OC)cc1
Yield: 23.5 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 150 mg (0.27 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-N-butyl-6-cyclohexyl-4-hydroxy-2-methylhexanamide [prepared as described in Example 6(a)] and 86 mg (0.28 mmole) of 2(R)-(4-methoxybenzyl)-3-(piperidinocarbonyl)propionic acid, to afford 47 mg of the title compound as a white powder, melting at 120°-122° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])=[C:35]([CH2:45][CH3:46])[CH:34]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[CH2:45]([C:35]1[CH:34]=[C:33]([C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:38]=[CH:37][C:36]=1[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH3:46]
Reactant: CCc1cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(-c2ccc(O)cc2)ccc1C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A tetra-n-butylammonium fluoride-11.0M tetrahydrofuran solution (0.39 ml, 0.391 mmol) was added to a solution of methyl 2-(4′-{[tert-butyl(dimethyl)silyl]oxy}-3-ethyl-1,1′-biphenyl-4-yl)propionate (104 mg, 283 mmol) obtained in Example (103-1) in tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 1.5 hours. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give methyl 2-(3-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)propionate (76 mg, 1009).
Reaction SMILES: CC(C)=O.[C:5]1(=O)[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]=[CH:9][CH:8]=[C:7]3[C:6]1=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[NH2:29])[C:23]([OH:25])=[O:24]>CN(C)C=O>[CH:8]1[C:7]2[C:6]3[C:5]([C:15]4[C:16]=2[C:11]([CH:12]=[CH:13][CH:14]=4)=[CH:10][CH:9]=1)=[N:19][C:20]1[C:28](=[CH:27][CH:26]=[C:22]([C:23]([OH:25])=[O:24])[CH:21]=1)[N:29]=3
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C1C(=O)c2cccc3cccc1c23
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
500 mL of dimethylformaldehyde was added to a mixture of 10 g of purified acenaphthenequinone and 84 g of 3,4-diaminobenzoic acid. The reactant continued to be stirred at room temperature for 21 hours. The precipitate was filtered to obtain a crude composition. This crude composition was dissolved in heated dimethylformamide, filtered again and purified by washing in dimethylformamide and water.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[O:3]1.I([O-])(=O)(=O)=O.[Na+].Cl>C1COCC1.O>[F:19][C:16]([S:15][C:12]1[CH:11]=[CH:10][C:9]([B:4]([OH:5])[OH:3])=[CH:14][CH:13]=1)([F:18])[F:17]
Reactant: CC1(C)OB(c2ccc(SC(F)(F)F)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a round-bottomed flask was added 4,4,5,5-tetramethyl-2-(4-trifluoromethylsulfanyl-phenyl)-[1,3,2]dioxaborolane (960 mg, 3.16 mmol) and sodium periodate (2.03 g, 9.48 mmol) in THF and water (4:1, 26 mL). The resulting suspension was stirred at rt for 30 min. HCl (1 N aq., 2.21 mL) was added to the suspension and the reaction mixture was stirred at rt for 18 h. The resulting precipitate was removed by filtration and washed with hexanes. The filtrate was diluted with water (25 mL) and extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (10 mL×2), and the combined organic layers dried (Na2SO4) and concentrated to yield the title compound (512 mg, 73%).
Reaction SMILES: [C:1](Br)([CH3:4])([CH3:3])[CH3:2].[Mg].[CH3:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10]>CCOCC>[C:8]([CH:9]([OH:10])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])([CH3:11])[CH3:7]
Reactant: CC(C)(C)Br
Reactant: CC(C)(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)C(O)C(C)(C)C

Procedure:
A solution of t-butyl bromide in ether is added slowly to magnesium stirrings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all the magnesium dissolves. At 0° C., a solution of 2,2-dimethylpropionaldehyde is added and the resulting product is quenched with 1M HCl and extracted with ether and the solvent is evaporated to afford di-t-butylmethyl alcohol.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=[C:6]2[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:6]2[CH:5]=[CH:4][NH:3]1
Reactant: CCOC(=O)c1cn2c(=O)[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(=O)[nH]ccc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 30.5 %

Procedure:
Ethyl 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate (2.510 mmol, 0.52 g) was suspended in ethanol (20 ml). Cesium carbonate (5.02 mmol, 1.635 g) dissolved in water (4 ml) was added and the resulting mixture was stirred at RT for 3.5 h after which the mixture was refluxed for 8 h. The ethanol was evaporated, and the residue was diluted with water. The pH was adjusted to 4 with 1 M HCl and the solvent was evaporated. The residue was purified by trituration from DMF. 0.137 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 7.17-7.31 (m, 2H), 7.86-7.99 (m, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1>CCO.[Pd]>[NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared by hydrogenation of {4-[4-(3-amino-3-methyl-but-1-ynyl)-phenyl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine using Pd/C in EtOH.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH2:13][C:14]1[C:15]([Cl:29])=[N:16][C:17]([Cl:28])=[CH:18][C:19]=1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH3:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](=O)[CH3:38])[CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[Cl:29][C:15]1[C:14]([N:13]=[C:37]([C@H:34]2[CH2:35][CH2:36][C@H:31]([CH3:30])[CH2:32][CH2:33]2)[CH3:38])=[C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:18]=[C:17]([Cl:28])[N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Reactant: CC(=O)[C@H]1CC[C@H](C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=Nc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
p-TsOH.H2O (3.4 g, 0.018 mol) was added to a mixture of tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate (85 g, 0.306 mol) and 1-(trans-4-methylcyclohexyl)ethanone (64 g, 0.46 mol) in toluene (1.3 L). The mixture was heated to reflux with a Dean-Stark trap for 14 h. TLC (petroleum/ethyl acetate=5:1) showed about ⅔ of tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate was consumed. The solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether) to give crude tert-butyl (2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethylidene)amino)pyridin-4-yl)carbamate.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[N:19]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:26]([OH:28])=[O:27])[C:18](=[O:33])[CH:17]=2)=[C:12]([CH2:36][NH:37][C:38]([O:40][CH3:41])=[O:39])[CH:11]=1>C(Cl)Cl>[Br:8][C:17]1[C:18](=[O:33])[N:19]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([OH:28])=[O:27])[C:20]([CH3:22])=[CH:21][C:16]=1[O:15][CH2:14][C:13]1[CH:34]=[CH:35][C:10]([F:9])=[CH:11][C:12]=1[CH2:36][NH:37][C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Reaction time: 1.5 h

Procedure:
NBS (0.69 g, 3.85 mmol) was added to a solution of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4) (1.75 g, 3.85 mmol) in DCM (45 mL). After 1.5 h, solvent removed on rotary evaporator. Solid dissolved in EtOAc and hexane added, resulting in a solid precipitate. Solid filtered. Solid subsequently dissolved in DCM and washed with water. Organic layer dried over Na2SO4, filtered, and concentrated. Pale yellow solid dried in vacuo (1.47 g, 72%). 1H NMR (CD3OD/400 MHz) δ8.04 (m, 1H), 7.77 (s, 1H), 7.54 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 533.0700 and 535.0677 (M+H calculated for C24H23BrFN2O6 requires 533.0718 and 535.0701).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1)#[N:3].C(N(CC)CC)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>ClCCl>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
The 4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (˜5.79 mmol) in dichloromethane (DCM) (50 mL) was cooled to 0° C. and treated with triethylamine (4.0 mL, 28.9 mmol), then 4-chlorophenylsulfonyl chloride (1.34 g, 6.37 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with dichloromethane (100 mL), washed with water (50 mL×3), dried over sodium sulfate and concentrated in vacuo to provide 3.22 g (97%) of the title compound as a yellow solid. M.p.=144-146° C.; 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.65 (br. s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.94 (dd, J=0.8 and 7.6 Hz, 1H), 7.82-7.85 (m, 1H), 7.77-7.75 (m, 2H), 7.67-7.64 (m, 3H), 7.44 (d, J=4.4 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 6.37 (d, J=4.8 Hz, 1H), 3.91 (bs, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.48-2.45 (m, 1H), 2.32 (t, J=10 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.41-1.36 (m, 1H). LCMS: 576 [M+H].
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][O:23][C:24](=[O:26])[CH3:25].[CH2:27]([C:29]([C:47]1[S:51][C:50]([S:52]([NH2:55])(=[O:54])=[O:53])=[C:49]([CH3:56])[CH:48]=1)([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH:40]([OH:45])[C:41]([CH3:44])([CH3:43])[CH3:42])=[C:34]([CH3:46])[CH:33]=1)[CH2:30][CH3:31])[CH3:28]>>[CH3:22][O:23][C:24](=[O:26])[CH3:25].[CH3:44][C:41]([CH3:42])([CH3:43])[C:40](=[O:45])[CH2:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]([C:47]2[S:51][C:50]([S:52]([NH2:55])(=[O:54])=[O:53])=[C:49]([CH3:56])[CH:48]=2)([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:33][C:34]=1[CH3:46]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: COC(C)=O
Product: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Yield: 96 %

Procedure:
Using the pyridinium dichromate oxidation analogous to Example 139C, (5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (96%). 1H NMR (CDCl3) δ 6.96, 7.02 (m, 3H), 6.59 (s, 1H), 5.22 (t, 1H), 3.83 (d, 1H, J=5.7 Hz), 3.65 (s, 3H), 2.82 (t, 2H), 2.72 (t, 2H), 2.40 (s, 3H), 2.27 (s, 3H), 2.07 (m, 4H), 1.10 (s, 9H), 0.68 (t, 6H);