Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 55.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 3-thienylboronic acid (92 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (57 mg, 55%)
Reaction SMILES: C([S:5][C:6]([CH3:9])([CH3:8])[CH3:7])(C)(C)C.Cl>[Cl-].[Zn+2].[Cl-].CS(C)=O>[C:6]([S:5][S:5][C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)SC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CS(C)=O
Product: CC(C)(C)SSC(C)(C)C
Yield: 42 %

Procedure:
When a mixture of 10 ml of di-t-butyl sulfide and 2.5 ml of dimethyl sulfoxide was heated at 300° F. (149° C.) for about 40 minutes in the presence of catalytic amounts of hydrochloric acid and zinc chloride a 42 percent yield of di-t-butyl disulfide was obtained, as indicated by gas-liquid chromatography.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:9]=[C:7]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCN
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: CCOC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(C)=O
Yield: 68 %

Procedure:
The (E)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step C) is coupled with ethyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield=68% (chromatography on silica, eluent: ether/petroleum ether 6/4) m.p.<50° C. IR (nujol): 3300, 1730, 1690, 1640, 1610 cm-1 1H NMR: (CDCl3 /TMS)=7.20, (s, 5H); 6.75 (s, 1H); 6.00 (broad s, 1H); 3.95 (q, 2H, J=6, 7 Hz); 3.85 (s, 2H); 3.40 (q app., 2H, J app.=6.2 Hz); 2.30 (t, 2H, J=6.7 Hz); 2.30 (s, 3H); 1.15 (t, 3H, J=6.7 Hz). Microanalysis: C17H21O4NS Calc. % C=60.87 H=6.31 N=4.18 Found. % C=60.12 H=6.22 N=3.92
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18].[CH3:19]O>>[ClH:18].[CH3:19][O:16][C:14]([C:11]1([CH3:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: Cl
Product: COC(=O)C1(C)CCNCC1
Reaction time: 18 h

Procedure:
To a stirred solution of 4-methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.10 mmol) in MeOH (2 mL) is added HCl (5 ml, 4 M in dioxane). After 18 h, the mixture is evaporated to dryness, the residue is dissolved in MeOH (3 mL), and the stirred solution is treated with Et2O (45 ml). The resulting solid is filtered and dried to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].C(OCC)(=O)C.[Br:18]N1C(=O)CCC1=O>CS(C)=O>[Br:18][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].CC1C=CC(S([CH2:22][N+:23]#[C-:24])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:24]=[N:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2cnco2)c1
Yield: 95.1 %

Procedure:
Intermediate X-a was prepared as for example I-c using 3-nitrobenzaldehyde (4 g, 26 mmol), TosMIC (5.7 g, 29 mmol) and K2CO3 (4.4 g, 32 mmol) in MeOH to give intermediate X-a as a yellow solid (4.7 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.50 (t, J=1.9 Hz, 1H), 8.21 (ddd, J=8.2, 2.3, 1.0 Hz, 1H), 8.17 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 7.99 (s, 1H), 7.78 (t, J=8.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11](/[CH:12]=[C:13]3\[O:14][C:15]4[C:22]([CH2:23][N:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[C:21]([OH:37])[CH:20]=[CH:19][C:16]=4[C:17]\3=[O:18])[C:6]2=[CH:5][CH:4]=1)#[CH:2].[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[ClH:38].[ClH:38].[C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11](/[CH:12]=[C:13]3\[O:14][C:15]4[C:22]([CH2:23][N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[C:21]([OH:37])[CH:20]=[CH:19][C:16]=4[C:17]\3=[O:18])[C:6]2=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 0.030 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.012 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][CH:18]=[CH:19]5)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2ccc3[nH]ccc3c2)cc1-c1nnc(C2CC2)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-Bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (200 mg, 0.71 mmol), 5-indolyl boronic acid (112 mg, 0.78 mmol), K2CO3 (290 mg, 2.13 mmol), 1,4-dioxane (10.0 mL) and water (4.0 mL) were taken in a sealed tube and degassed with nitrogen for 15 min. Then Pd(PPh3)4 (41 mg, 0.03 mmol) was added and stirred for 18 h at 100° C. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated under reduced pressure to get crude 3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-(1H-indol-5-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 30% EtOAc in petroleum ether to afford the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[OH:13]
Reactant: O=S(=O)(O)O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(O)c1
Reaction time: 0.17 h

Procedure:
A solution of 3.2 grams of 2-fluoro-5-nitroaniline, sulfuric acid (3 cc., d 1.84) and 8 ml. of water is stirred into a solution of 1.5 grams of sodium nitrite in water, maintained below 5° C. After 10 minutes, the excess nitrous acid is destroyed by urea, the reaction mixture filtered, and the filtrate added to 40 ml. of boiling 50% sulfuric acid. After complete addition, the mixture is boiled an additional 15 minutes, cooled, and the separated phenol filtered and washed with water. It is then purified by recrystallization from hexane.
Reaction SMILES: B.O1CCCC1.[CH2:7]([CH:9]1[O:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:12][N:11]([CH2:23][CH2:24][CH3:25])[C:10]1=O)[CH3:8]>C1COCC1>[CH2:7]([CH:9]1[O:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:12][N:11]([CH2:23][CH2:24][CH3:25])[CH2:10]1)[CH3:8]
Reactant: CCCN1CC(c2cccc(OC)c2)OC(CC)C1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CC(CC)OC(c2cccc(OC)c2)C1
Temperature: 85 °C

Procedure:
Borane-tetrahydrofuran complex (1M in THF) (3 mL, 3 mmol) was added dropwise to the product from example 45 (0.33 g, 1.18 mmol) in dry THF (4 mL) under an atmosphere of nitrogen. The reaction mixture was heated at 85° C. for 3 hours then cooled and quenched by the addition of methanol (1 mL). The reaction mixture was then concentrated in vacuo and the residue suspended in 6N HCl (aq) (10 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was cooled and extracted with diethyl ether (2×10 mL). The aqueous layer was rendered basic (pH 9-10) by addition of solid potassium carbonate before re-extracting with dichloromethane (2×15 mL). The dichloromethane extracts were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the crude products as a clear oil. Purification by column chromatography on silica eluting with ethyl acetate, pentane (1:10) yielded the two title compounds as single diastereomers.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH2:35])=[CH:28][CH:27]=1>O1CCOCC1.CC(N(C)C)=O>[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH:35][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:28][CH:27]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(I)c2c1OCO2
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ccc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 70.6 %

Procedure:
4.0M HCl in Dioxane (0.37 ml) was added to a stirred suspension of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (500 mg) and 7-iodo-1,3-benzodioxol-4-amine (0.39 g) in DMA (1 ml). The resultant mixture was stirred and heated to 80° C. for 10 mins. A grey precipitate was formed which was filtered and washed with further DMA followed by diethyl ether and dried to give N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine as a beige solid (0.59 g); NMR Spectrum: (DMSOd6) 2.29-2.37 (m, 2H); 3.03-3.14 (m, 2H); 3.22-3.30 (m, 2H), 3.40-3.51 (m, 2H), 3.78-3.88 (m, 2H), 3.94-4.00 (m, 5H), 4.31 (t, 2H), 6.11 (s, 2H), 6.80 (d, 1H), 7.27 (d, 1H), 7.41 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H); Mass Spectrum: M+H+ 562.9.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: CCN(CC)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(CC)CCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirring, refluxing suspension of 84.4 g (0.4) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 750 ml ethanol was aded gradually a solution of 2-diethylaminoethylamine in 50 ml ethanol. The solution was refluxed and stirred for 1 hr; the solvents were then removed in vacuo. The residue was taken up in 300 ml chloroform; the solution was washed with three 150-ml portions of water, dried over magnesium sulfate, and concentrated to dryness in vacuo to give 123 g (100%) of the product.
Reaction SMILES: [CH:1]1(/[C:4](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5]\[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[CH:5]=[C:4](\[CH:1]2[CH2:3][CH2:2]2)/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)C2CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
As in Example 115, (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid (2.7 g) and 4-nitrophenol (1.844 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.3 g) and the mixture was stirred at room temperature overnight. After the usual work up, the ester was crystallized from 2-propanol to yield 2.8 g of (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester. mp 111°-112.5° C.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[N:14]1[C:18]([NH:19][C:20](=[O:25])[CH2:21][O:22][CH2:23][CH3:24])=[C:17]([S:26]([C:28]([F:31])([F:30])[F:29])=[O:27])[C:16]([C:32]#[N:33])=[N:15]1.[CH3:34]Br>C(#N)C>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([Cl:2])[C:4]=1[N:14]1[C:18]([N:19]([CH3:34])[C:20](=[O:25])[CH2:21][O:22][CH2:23][CH3:24])=[C:17]([S:26]([C:28]([F:31])([F:29])[F:30])=[O:27])[C:16]([C:32]#[N:33])=[N:15]1
Reactant: CBr
Reactant: CCOCC(=O)Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [K]
Solvent: CC#N
Product: CCOCC(=O)N(C)c1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a suspension of the potassium salt of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-(ethoxyacetamido)pyrazole, prepared in Step 1 above, (18.9 g, assay=75.6%, 0.026 mol) in 56.8 g of acetonitrile, a solution of methyl bromide in acetonitrile (86.5 g, conc=28%, 0.255 mol) was added. The mixture was stirred during 6 hours at 60° C. and then concentrated to dryness. The residue was solubilized in a mixture of toluene (100 g) and water (100 g). The organic layer was washed with 100 g of water and concentrated to a 38% solution, heated to 80° C. and product was recrystallized in a 40/60 toluene/n-heptane solution to afford 10.3 g of a white solid (yield=64%, assay=85%).
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]=[C:1]=[O:4])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](N=C=O)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(+1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to Tint=2-3° C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ˜6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at Tint=2-5° C. for 30 min, at which point HPLC analysis indicates >99 A % conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ˜1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4% yield). 1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.53 (d, J=11.4 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H). The material was used in Step 3 without further purification.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=O)C.[H-].[Na+].[C:24]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH2:27][CH3:28])([CH3:26])[CH3:25]>CC(N(C)C)=O.O>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:35]([C:32]2[CH:33]=[CH:34][C:29]([C:24]([CH2:27][CH3:28])([CH3:25])[CH3:26])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[N:10]([CH3:21])[N:9]=1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc(C)cc3)c(OCCO)nn2C)cc1
Reaction time: 2 h

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (1.0 g) in dimethylacetamide (10 ml) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 415 mg) followed by 4-tert-amylbenzenesulphonyl chloride and (938 mg), the mixture was stirred for 2 hrs. The reaction was diluted with water (50 ml) and extracted with dichloromethane (5×30 ml). The crude mixture was dissolved in ethanol (50 ml) and sodium hydroxide (2N, 5 ml) was added, the mixture was stirred at room temperature for 48 hrs and then neutralised to pH 7 by addition of hydrochloric acid (2N) and extracted with dichloromethane (2×50 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (290 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8]Cl.[Br-:11].[Li+].CCCCCCC>O>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][Br:11]
Reactant: COC(=O)C=CCCCCl
Reactant: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Product: COC(=O)C=CCCCBr
Reaction time: 6 h
Yield: 83 %

Procedure:
In an atmosphere of nitrogen, 6-chloro-2-hexenoic acid methyl ester (4Cl); 188.8 g {GC purity; 83.6%, pure amount; 157.9 g (0.971 mol)}, lithium bromide (126.5 g, 1.457 mol) and heptane (16 ml) were added to a 500 ml capacity flask, followed by stirring for 6 hours under heptane reflux. After completion of the reaction, heptane was added as an extraction solvent and water was added thereto to separate the organic layer. The solvent was evaporated under a reduced pressure using an evaporator, and then the residue was distilled under a reduced pressure (70 to 80° C./0.1 ton) to obtain 6-bromo-2-hexenoic acid methyl ester (4Br); 203.4 g {GC purity; 82.3%, pure amount (4Br); 167.5 g (0.809 mol, yield 83%/(4Cl)}.
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:26]([C:33]#[N:34])([CH3:32])[C:27]([O:29]CC)=O)=[C:17]([C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=1>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:18]=[C:17]2[C:16](=[CH:15][CH:14]=1)[C:26]([C:33]#[N:34])([CH3:32])[C:27](=[O:29])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]2[OH:9]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C(C)(C#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.16 g, 1.3 mmol) in DMF (3 mL) was added dropwise to a stirred suspension of 60% NaH (0.033 mL, 1.3 mmol) in dry 1,4-dioxane (5 mL) under a nitrogen atmosphere at room temperature. After 30 minutes, a solution of ethyl 3-(5-chloro-2-(2-cyano-1-ethoxy-1-oxopropan-2-yl)phenyl)propiolate (0.445 g, 1.3 mmol) in DMF (3 mL) was added dropwise. The reaction was monitored by LC-MS and, when complete, the solvent was removed. The residual brown oil was dissolved in DCM (50 mL), water (30 mL), and AcOH (2 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude residue was purified using silica flash chromatography with a gradient of 10-50% EtOAc/hexanes. MS m/e=306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([CH:29]=1)[O:21][CH2:22][C:23]1[N:24]([CH3:28])[N:25]=[CH:26][N:27]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([O:21][CH2:22][C:23]4[N:24]([CH3:28])[N:25]=[CH:26][N:27]=4)[CH:29]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: Cn1ncnc1COc1cc(Br)ccc1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: Cn1ncnc1COc1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 43 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3-(5-bromo-2-fluorophenoxymethyl)-2-methyl-2H-[1,2,4]triazole as described in Example 6 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (169 mg, 43%): δH (400 MHz, d6-DMSO) 1.58 (6H, d, J 1), 3.94 (3H, s), 5.53 (2H, s), 5.55 (1H, s), 7.21-7.29 (2H, m), 7.44 (1H, dd, J 11 and 9), 7.68 (1H, dd, J 8 and 2), 7.76 (1H, s), 7.98 (1H, s), 8.42 (1H, d, J 7); m/z (ES+) 400 [MH+].