Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH3:34][C:35]1([CH3:41])[CH2:40][O:39][CH2:38][CH2:37][NH:36]1>ClCCl.CN(C=O)C.C1COCC1>[CH3:34][C:35]1([CH3:41])[CH2:40][O:39][CH2:38][CH2:37][N:36]1[C:16]([C:13]1[N:14]=[CH:15][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:11][N:12]=1)=[O:18]
Reactant: CC1(C)COCCN1
Reactant: O=C(O)c1ncc(C#Cc2cccc(Cl)c2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1C(=O)c1ncc(C#Cc2cccc(Cl)c2)cn1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
(100 mg, 0.39 mmol) 5-(3-Chloro-phenylethynyl)-pyrimidine-2-carboxylic acid (Example 4, step 1) was suspended in dichloromethane (1 ml) and DMF (10 μl). Oxalyl chloride (51 μl, 0.59 mmol, 1.5 equiv.) was added drop wise at room temperature and the mixture was stirred for 1 hour at reflux. The reaction mixture was then added to a mixture of diisopropylethylamine (235 μl, 1.34 mmol, 3.3 equiv.) and 3,3-dimethylmorpholine (46 mg, 0.40 mmol, 1 equiv.) in THF (2 ml). The mixture was stirred for 16 hours at room temperature and evaporated in presence of Isolute® sorbent to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0→0:100. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone (120 mg, 94% yield) was obtained as a white solid, MS: m/e=356.6/358.6 (M+H+).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:19](=[O:22])(=[O:21])[NH2:20])[CH2:6]1)(=O)C.C[O-].[Na+].C1(C)C=CC=CC=1.Cl>ClCCl.CO.O>[C:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([SH:4])[CH2:6][C@@H:7]1[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:19](=[O:22])(=[O:21])[NH2:20])=[O:11])([CH3:15])([CH3:16])[CH3:14]
Reactant: CC(=O)S[C@H]1C[C@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N(C(=O)OC(C)(C)C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](S)C[C@@H]1CN(C(=O)OC(C)(C)C)S(N)(=O)=O

Procedure:
To a solution of (2R,4S)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine (i.e., a substrate) in dichloromethane, 4.92M sodium methoxide (NaOMe) in methanol is added. The mixture is stirred. The conditions for this reaction are shown in Table 3, Step A-7. The reaction mixture is diluted with water. The water layer is taken, toluene is added thereto, and acidified with conc. hydrochloric acid under ice cooling. The organic layer is taken, successively washed with water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give (2R,4S)-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methyl-4-mercaptopyrrolidine. mp. 90.0° to 91.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].[H-].[Na+]>CN(C=O)C>[CH3:12][N:13]([CH3:17])[C:14]([O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:15]
Reactant: COc1cc(O)cc(OC)c1
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(OC(=S)N(C)C)c1

Procedure:
3,5-Dimethoxyphenol is reacted with N,N-dimethylthiocarbamoyl chloride in the presence of sodium hydride in DMF to give 1-dimethylaminothiocarbonyloxy-3,5-dimethoxybenzene of m.p. 77°-78°. This product is rearranged, by heating for half an hour at 270°, to give 1-dimethylaminocarbonylmercapto-3,5-dimethoxybenzene, which, in the crude state, by leaving to stand for 3 days with ethanolic KOH, is saponified to give 3,5-dimethoxythiophenol of b.p. 103°-109°/0.25 mm. Reaction with glutaconic acid dimethyl ester gives 3-(3,5-dimethoxyphenylmercapto)-glutaric acid dimethyl ester, which is converted, at 80° by means of polyphosphoric acid, into 5,7-dimethoxy-thiochroman-4-one-2-acetic acid methyl ester of m.p. 98°-99°. The corresponding free acid (m.p. 180°-182°) is converted, via the chloride and the amide (m.p. 199°-202°), into the corresponding nitrile (m.p. 123°-124°), which is split, by means of BBr3, into 5-hydroxy-7-methoxy-thiochroman-4-one-2-acetonitrile (m.p. 97°-98°). Analogously to Example 1, there are obtained therefrom 5-hydroxy-7-methoxy-thiochroman-4-one-2-acetaldehyde (m.p. 112°-115°), 2-phenyl-4-[2-(5-hydroxy-7-methoxy-thiochroman-4-on-2-yl)-ethylidene]-2-thiazolin-5-one (m.p. 97°-99°), 4-thiobenzamido-1,4,4a,5,5a,6,11,12-octahydro-3,10,12-trihydroxy-8-methoxy-1,11-dioxo-6-thianaphthacene-2-carboxamide (mixture of stereo-isomers), 4-de-dimethylamino-4-thiobenzamido-8-methoxy-12a-dehydroxy-6-thiatetracycline (m.p. 212°-215°) and, finally, by hydroxylation
Reaction SMILES: [CH3:1][C:2]1[N:11](COC(=O)C(C)(C)C)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:21][N:22]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[CH2:23][CH2:24][O:25]C(=O)C)[CH:8]=2)[N:3]=1.[N+:38]([C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH2:45])([O-:40])=[O:39]>>[CH3:1][C:2]1[NH:11][C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:21][N:22]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([NH:45][CH2:44][C:43]4[CH:46]=[CH:47][CH:48]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=4)=[O:34])=[CH:36][CH:37]=3)[CH2:23][CH2:24][OH:25])[CH:8]=2)[N:3]=1
Reactant: CC(=O)OCCN(Cc1ccc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1nc2ccc(CN(CCO)c3ccc(C(=O)NCc4cccc([N+](=O)[O-])c4)cc3)cc2c(=O)[nH]1
Yield: 46 %

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-2-methyl-4-oxo-3-pivaloyloxymethylquinazolin-6-ylmethyl)-N-(2-acetoxyethyl)amino]benzoic acid was reacted with 3-nitrobenzylamine to give p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(2-hydroxyethyl)amino]-N-(3-nitrobenzyl)benzamide (containing 1 equivalent of water) in 46% yield, m.p. 230°-232° C.
Reaction SMILES: [CH2:1]([NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:11]([OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCOCC>O>[OH:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][C@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6]2
Reactant: CCCN[C@H]1CCc2c(O)cccc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCN(C(=O)OCc1ccccc1)[C@H]1CCc2c(O)cccc2C1
Yield: 81.3 %

Procedure:
A stirring suspension of (S)-6-propylamino-5,6,7,8-tetrahydro-l-naphthalenol (7.34 g, 0.0257 mol) in water (100 mL) was cooled in an ice bath and sodium bicarbonate (8.49 g, 0,101 mol) was added. This suspension was stirred for fifteen minutes then benzyl chloroformate (4.50 g, 0.0264 mol) was added dropwise. The mixture was stirred for fifteen minutes and then allowed to come to room temperature. Ether (100 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate, once with water, twice with dilute hydrochloric acid, once with water and once with saturated aqueous sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure to give 7.09 g (81% yield) of product as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:24]([NH:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred cold mixture of ethyl 2-amino-4-phenylthiazole-5-carboxylate (1.24 g, 5.00 mmol), 4-dimethylaminopyridine (0.10 g, 16 mol %) and pyridine (4.0 mL, 10 equiv) in dichloromethane (20.0 mL) was added benzoyl chloride (0.70 g, 5.00 mmol) in dichloromethane (3 mL). The mixture was stirred at ambient temperature for 2 h, then washed with 5% hydrochloric acid solution, water, and dried over anhydrous sodium sulfate. Removal of the solvent afforded the title compound in 92% yield (1.62 g); 1H NMR (CDCl3, 300 MHz) δ 10.10 (s, 1H), 8.15 (d, J=7.2 Hz, 2H), 7.85-7.45 (m, 8H), 4.24 (q, J=5.9 Hz, 2H), 1.19 (t, J=5.9 Hz, 3H); MS (ES+) m/z 353.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=2)[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (0.15 g, 0.54 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (from Frontier, 0.14 g, 0.59 mmol), sodium carbonate (110 mg, 1.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (52 mg, 0.064 mmol) in acetonitrile (4 mL)/water (1 mL) was degassed and then refilled with N2. The reaction was stirred at 95° C. for 2 h, cooled, diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, and then dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 40% EtOAc in hexanes, to give the desired product (114 mg, 70%). LCMS calculated for C16H16ClN2O2 (M+H)+: m/z=303.1; Found: 303.0
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)=[C:4]([C:15]#[N:16])[CH:3]=1.[Cl:17]OC(C)(C)C.O.BrC1NC(C2C=CC(Cl)=C(Cl)C=2)=C([N+]([O-])=O)C=1>O1CCCC1>[Br:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)=[C:4]([C:15]#[N:16])[C:3]=1[Cl:17]
Reactant: CC(C)(C)OCl
Reactant: N#Cc1cc(Br)[nH]c1-c1ccc(Cl)c(Cl)c1
Agent: O=[N+]([O-])c1cc(Br)[nH]c1-c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Br)c1Cl
Reaction time: 8 h

Procedure:
A sample of 5-bromo-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (0.158 g, 0.005 mole) is dissolved in tetrahydrofuran (5 mL). An equivalent amount of t-butyl hypochlorite is added and the solution stirred overnight. The solution is poured into water and the precipitate (0.052 g, 30%) is collected. The mp is >275° C. In a similiar fashion one can prepare 2-bromo-3-chloro-5-(3,4-dichlorophenyl)-4-nitropyrrole by starting with 2-bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 4-[(2,2-dimethylpropyl)(2-oxoethyl)amino]-2-(trifluoromethyl)benzonitrile (0.882 g, 2.96 mmol) in MeOH (10 mL) at 0° C. was added NaBH4 (0.112 g, 2.96 mmol) in one portion and the mixture was stirred overnight, slowly warming to rt. The mixture was cooled to 0° C., sat'd NH4Cl (1 mL) was added and the mixture was concentrated in vacuo. The residue was partitioned between EtOAc/water and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.829 g of the title compound as a colorless syrup which solidified on standing: MS (ESI) m/z 301 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]1([C:32]#[CH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([C:33]#[C:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C#Cc2ccccc2)ccc1O

Procedure:
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide and phenylacetylene as the raw materials, the same operation as the example 66 gave the title compound.
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26]>O1CCCC1>[CH:1]1([CH:4]([OH:5])[C:25]([F:27])([F:26])[F:24])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CC1)C(F)(F)F
Yield: 26.8 %

Procedure:
According to Reference Example 8-12, by use of cyclopropanecarbaldehyde (300 mg, 4.28 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.856 mL, 0.856 mmol) and (trifluoromethyl)trimethylsilane (0.759 mL, 5.14 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by extraction gave 1-cyclopropyl-2,2,2-trifluoroethanol (Compound EB) (161 mg, yield: 27%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(C(CCCCCCCCCC)C[OH:22])CCCCCCC>>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:22])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Product: O=C(O)c1ccccc1C(=O)O
Reaction time: 0.17 h

Procedure:
Phthalic anhydride (52 g) was added to 2-octyldodecanol (90 g) and the mixture was stirred and heated to 140° for 1 hour and then rapidly to 190° for 10 minutes and then cooled. The mixture was filtered to remove excess phthalic anhydride and any phthalic acid formed, yielding 2-(2'-octyldodecyloxycarbonyl)benzoic acid (110 g).
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[CH3:29][CH:30]1[CH2:32][CH:31]1[CH2:33]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[O:28][CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Reactant: CC1CC1CO
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
2.55 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.40 g of 2,5-dimethyl-4-nitrophenol, 0.72 g of (2-methylcyclopropyl)methanol, 2.64 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 1.64 g of 2,5-dimethyl-1-[(2-methylcyclopropyl)methoxy]-4-nitrobenzen e.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O.O1CCOCC1.O1CCOCC1>[C:25]1([S:31]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[C:3]([OH:5])=[O:4])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(CCCCCCCc1ccc2c(n1)NCCC2)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CCCCCCCc1ccc2c(n1)NCCC2)NS(=O)(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 13-9 (0.27 g, 0.88 mmol) in H2O/dioxane (2:1, 4.4 mL) was cooled to 0° C. and then treated dropwise with 1N NaOH to attained a pH of 10.5. The reaction mixture was then treated with with PhSO2Cl (0.23 g, 1.3 mmol) in dioxane (750 μL) while maintaining a pH of 10.5 by adding 1N NaOH. After 15 min, the pH was adjusted to 7 with 1N HCl to effect a white precipitate. The precipitate was collected by filtration and triturated with EtOAc and then ether to give 13-10 as a colorless solid.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:27]=[C:28]([O:30][CH:31]([CH3:33])[CH3:32])[CH:29]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=2)=[O:13])C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][CH:31]([CH3:33])[CH3:32])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=1)=[O:13]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 20 h
Yield: 107.9 %

Procedure:
To a solution of tert-butyl 3-[(3-phenylmethoxy-5-propan-2-yloxy-benzoyl)amino]pyrazole-1-carboxylate (76.4 g) in methanol (764 ml) was added 10% palladium on carbon (7.6 g) and the resulting mixture was stirred under an atmosphere of hydrogen at a pressure of 5 bar for 20 hours. The catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum to leave a solid (66 g). This was purified by flash chromatography on silica, eluting with ethyl acetate in isohexane (10 to 70%) to give the title compound (56.4 g).
Reaction SMILES: [CH:1]1([NH:4][C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1>>[CH:1]1([N:4]([C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([N:27]3[C:23]([CH3:22])=[N:24][N:25]=[N:26]3)=[CH:29][CH:30]=2)[CH2:2][CH2:3]1
Reactant: F[C@H]1CN(c2ccc(C(F)(F)F)cn2)CC[C@H]1NC1CC1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)[C@@H]2CCN(c3ccc(C(F)(F)F)cn3)C[C@@H]2F)cc1

Procedure:
The title compound is prepared from (3S,4R)-cyclopropyl-(3-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.26 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3](=[O:20])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:46])[C@@H:35]([NH2:45])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][CH2:29]1)=[O:27])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:23]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34](=[O:46])[C@@H:35]([NH:45][C:17]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][C:3](=[O:20])[C:2]([CH3:1])([CH3:22])[CH3:21])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)=[O:19])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:32][CH2:33]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CNC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.7 g of 5-(3,3-Dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carboxylic acid and 2.0 g of 4-((S)-2-Amino-3-tert-butoxycarbonylamino-propionyl)-piperazine-1-carboxylic acid ethyl ester in 10 ml of DMF, 0.9 g of HOBT and 1.1 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 3.8 g.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O1CCCC1.Cl>O1CCCC1>[CH:15]1([CH:7]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:3][C:2]=2[CH3:1])[OH:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1sc(-c2ccccc2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(O)C1CCCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-methyl-5-phenylthiophene-3-carbaldehyde (1.72 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (12.8 mL) at 0° C., and the mixture was stirred for 2 hr. 1.0M Cyclohexylmagnesium bromide-tetrahydrofuran solution (5 mL) was added dropwise again, and the mixture was further stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (2.33 g, 96%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:11]1[S:12][C:13](/[CH:16]=[CH:17]/[C:18]2[O:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[CH:14][N:15]=1>C1COCC1>[C:23]([C:20]1[O:19][C:18](/[CH:17]=[CH:16]/[C:13]2[S:12][C:11]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]3[NH2:1])=[N:15][CH:14]=2)=[N:22][CH:21]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cnc(/C=C/c2cnc(Br)s2)o1
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc(/C=C/c2cnc(N3C=CC=CC3N)s2)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-aminopyridine (238 mg, 2.56 mmol) in THF (8 mL) under argon was added sodium hydride (100 mg of 60% oil dispersion, 2.5 mmol) and the reaction stirred at 60 deg C. for 15 minutes, cooled to room temperature and 2-bromo-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazole] (200 mg, 0.64 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes, quenched with hydrochloric acid, washed with water and extracted with ethyl acetate. The organic layers were separated and concentrated to give a crude product which was heated with ethyl acetate: hexanes (1:1), cooled, filtered, and dried under vacuum to give the desired product. C17H18N4OS, MS m/e 327 (M+H)+. HPLC-HI 100% at 4.24 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).