Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]([CH3:25])=[CH:9][CH2:10][C:11]1[C:12]([OH:24])=[C:13]2[C:17](=[C:18]([CH3:22])[C:19]=1[O:20][CH3:21])[CH2:16][O:15][C:14]2=[O:23])(=[O:6])[O:4]C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:24][C:12]1[C:11]([CH2:10][CH:9]=[C:8]([CH3:25])[CH2:7][P:3](=[O:2])([OH:6])[OH:4])=[C:19]([O:20][CH3:21])[C:18]([CH3:22])=[C:17]2[C:13]=1[C:14](=[O:23])[O:15][CH2:16]2
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(OC)OC)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonic acid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) was added TMSBr (63 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) at 0° C. The reaction solution was allowed to warm to room temperature and stirred for 2 hours when completion of the reaction was observed by LCMS. The reaction was cooled to 0° C. and quenched by the addition of MeOH. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O-acetonitrile (5-0%) over 20 minutes to provide 12.2 mg (73%) of the product. 1H NMR (300 MHz, CD3OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48 (d, 2H, J=22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38 (q, 1H, J=7 Hz), 6.87 (br s, 1H) ppm; MS (m/z) 341 [M−H]−.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:9](Br)[CH:10]=[CH2:11].[Cl-].[NH4+]>C1COCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH2:3][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: CC(C)CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under a protective gas, 20 g. (0.82 gram atom) of magnesium filings in 150 ml. of tetrahydrofuran is charged into a 1-liter three-necked flask. Within about 60 minutes, 120 g. (0.73 mole) of 1-bromo-4-methylpentane in 270 ml. of tetrahydrofuran is added dropwise to the reaction mixture so that a reaction temperature of 60° C. evolves. The agitation is continued for another 11/2 hours at 50° C. The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette and transferred into a dropping funnel placed on top of a 2-liter three-necked flask. This flask is to be used for dissolving 84.0 g. (0.7 mole) of allyl bromide in 620 ml. of tetrahydrofuran and for combining this solution with 2.5 millimoles of Li2CuCl4 (as a 0.1-molar solution in THF). Within 60 minutes, the Grignard solution is to be dropped under stirring to this mixture, which latter has been cooled to -10° to -5° C. The reaction mixture is maintained at 0° C. for another 11/2 hours before Grignard compound is gently decomposed with saturated ammonium chloride solution (or about 50 ml. of water). The organic phase is separated, the residue is extracted repeatedly with ether, and the combined, olefin-containing phases are dried over sodium sulfate. After the solvents have been evaporated, 7-methyl-1-octene can be obtained in the pure form by fractionation over a Vigreux attachment or a column:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH:38]2[CH2:40][CH2:39]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:38]1([NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH2:40][CH2:39]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 568.0 [(M-H−]; mp 232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(OC)nc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.50 g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g) as starting materials, N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in ether, and 4N-hydrochloric acid/dioxane was added. The precipitated solid was collected by filtration to give N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide monohydrochloride (0.47 g).
Reaction SMILES: O[CH:2]1[CH2:5][C:4]([CH2:20][C:21]#[N:22])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.COCCN(CCOC)S(F)(F)[F:29].C(O)C>ClCCl>[F:29][CH:2]1[CH2:5][C:4]([CH2:20][C:21]#[N:22])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1
Reactant: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(F)C1

Procedure:
A solution of 3-hydroxy-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.01 g, 0.00003 mol) (a mixture of cis/trans isomers) in dichloromethane (3 mL), contained in a Teflon bottle equipped with a nitrogen inlet tube and stirring bar, was treated with 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (0.03 mL, 0.0002 mol) at rt. Ethanol (0.002 mL, 0.00003 mol) was added, and the mixture was stirred at rt over weekend. The reaction was evaporated to dry and the residue was purified with prep. HPLC (pH=10) to give a mixture of two isomers. LCMS calculated for C15H14FN6(M+H)+: 297.1. Found: 297.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1.C(Cl)Cl>[C:26]([NH:30][C:31]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH2:18][NH:17][C:15]2[C:14]([F:25])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:8][CH:9]=3)[N:16]=2)[CH2:20]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)NC(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 12a, (0.013 g, 0.036 mmol) in mixture of pyridine/CH2Cl2 (1 mL of 1:1 mixture was added tert-butyl isocyanate (0.005 mL, 0.046 mmol). The reaction mixture was stirred at 40° C. for 12 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 20.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[N:4][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:7]=1.O.NN>C(Cl)Cl>[NH2:8][C:5]1[N:4]=[C:3]([CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOP(=O)(Cc1nc(N2C(=O)c3ccccc3C2=O)ccc1Cl)OCC
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cc1nc(N)ccc1Cl)OCC

Procedure:
Following the procedure from Example 16, the product from Example 27 (1.0 g, 2.4 mmol) was reacted with hydrazine monohydrate (0.121 g, 2.4 mmol) in CH2Cl2 (25 mL). Workup produced the crude title product which was used without further purification.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Si:9]([O:26][CH2:27][C@H:28]([OH:35])[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(#N)C>[Si:9]([O:26][CH2:27][C@@H:28]1[O:35][C:2](=[O:3])[C:31]2=[N:32][CH:33]=[CH:34][N:30]2[CH2:29]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OC[C@H]1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Slowly add trichloromethyl chloroformate (5.80 mL; 2.0 equiv; 48.35 mmoles) over 15 minutes to a 0° C. solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (9.2 g; 1.0 equiv; 24.17 mmoles) and pyridine (15.64 mL; 8 equiv; 193.40 mmoles) in acetonitrile (450 mL). Stir for 1 hour and then allow the solution to warm to ambient temperature over 1 hour. Add water (30 mL) and concentrate the reaction mixture. Add dichloromethane (50 mL), and slowly pour the resulting solution into 50% saturated sodium bicarbonate (200 mL). Separate the layers and further extract the aqueous layer with dichloromethane (3×150 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purification by column chromatography (10% to 100% ethyl acetate in hexanes) affords the desired (6R)-6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (5.50 g; 56%). MS (m/z): 407(M+1).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25])[C:15]=3[OH:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:35]=[C:34]([Br:36])[CH:33]=[C:32]([Br:37])[C:31]=1[OH:38].C(N(CC)CC)C>C1COCC1>[CH:1]1[C:13]2[N:12]([C:14]3[C:15]([OH:27])=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[C:32]([Br:37])[C:31]=3[OH:38])[CH3:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CNCCN(C)Cc1cccc(-n2c3ccccc3c3ccccc32)c1O
Reactant: Oc1c(Br)cc(Br)cc1CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCN(C)Cc1cccc(-n2c3ccccc3c3ccccc32)c1O)Cc1cc(Br)cc(Br)c1O
Reaction time: 8 h
Yield: 56.9 %

Procedure:
2 (0.218 g, 0.606 mmol) and 2-bromomethyl-4,6-dibromophenol (0.209 g, 0.606 mmol) were dissolved in 20 mL of THF. Triethylamine (1.2 mL, 8.61 mmol) was added to the slightly pink solution. A white precipitate formed immediately. The reaction was allowed to stir overnight after which time the volatiles were removed and methanol added to make a slurry. The solids were filtered and dried under vacuum resulting in a white solid (0.215 g, 57% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15]>>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH:19][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13])[CH3:15]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Product: CCN(CC)CCNC(=O)CN1CCC(O)C1=O

Procedure:
3.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 3.7 g of 2-(diethylamino)ethylamine are heated to 95°-100° for 3.5 hours under nitrogen. The mixture is chromatographed on 45 g of aluminum oxide (neutral, activity grade III). The crude (R/S)-N-[2-(diethylamino)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride and ethyl acetate is again chromatographed on 25 g of aluminum oxide (neutral, activity grade III). The product which is eluted with ethyl acetate and ethanol is distilled in a bulb-tube at about 250°/0.03 mmHg.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:9]=[N:10]2.[NH3:21]>CO>[Cl:15][C:14]1[C:5]([CH2:4][C:3]([NH2:21])=[O:2])=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7]2
Reactant: N
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)cc12
Solvent: CO
Product: CN(C)Cc1cnc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94 %

Procedure:
A solution of (6-chloro-3-dimethylaminomethyl-quinolin-5-yl)-acetic acid methyl ester (462 mg, 1.58 mmol) in a mixture of methanol (4 mL) and liquid ammonia (20 mL) was stirred for 4 days in an autoclave at room temperature. After careful evaporation of the ammonia, the remaining solvent was evaporated in vacuo to afford the title compound as a pale brown solid (413 mg, 1.48 mmol, 94%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=8.85 (d, J=2.0 Hz, 1H), 8.31 (bs, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.75 (d, J=9.1 Hz, 1H), 7.62 (bs, 1H), 7.08 (bs, 1H), 4.10 (s, 2H), 3.67 (bs, 2H), 2.23 (bs, 6H). MS (ES+): 278 (M(C14H1635ClN3O)+H)+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][CH:28]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[I:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:32][CH:31]=1
Reactant: Ic1ccc(CCCCCCCCCCCCCCCCCCOCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Reaction time: 2 h

Procedure:
Finally, to a solution of 1-benzyloxy-18-(p-iodophenyl)octadecane (Compound V) (185 mg; 0.33 mmol) and anisole (0.15 ml; 1.32 mmol) in dichloromethane (3 ml) was added anhydrous aluminum chloride (135 mg; 1 mmol) at the room temperature. Stirring was continued for 2 h. The reaction was quenched by diluted hydrochloric acid and extracted by chloroform. Extract was dried (Na2SO4) and evaporated. The residue was chromatographed in hexane-ethyl acetate (gradient from 95:5 to 85:15) to give 18-(p-iodophenyl) octadecanol, Compound VI (123 mg; 77%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1c(O)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A 250 ml single neck round bottom flask was charged with 5.25 g (21 mmole) of methyl 7-hydroxy-8-n-propylchroman-2-carboxylate, 150 ml of dimethylformamide, 3.59 g (26 mmole) of anhydrous potassium carbonate, and 4.30 g (25 mmole) of benzyl bromide. The flask was stoppered and stirred (magnetic stirrer) at room temperature for 4 hours. The insoluble solids were separated by filtration and the dimethylformamide removed by rotary evaporation. The residue was dissolved in 200 ml ethyl acetate, clarified by filtration, and concentrated to an oily residue by rotary evaporation. The resultant crude material was purified by high pressure liquid chromatography (5% ethyl acetate-hexane), to obtain 5.48 g (77%) of the title compound as a clear oil. Calc: C, 74.09; H, 7.11; Found; C, 74.11; H, 7.06.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N+:24]([O-])=O)=[C:18]([N+:21]([O-])=O)[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([NH2:24])=[C:18]([NH2:21])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2cc1N

Procedure:
1-(3-Chloro-5-trifluoromethylpyridin-2-yl) -5,6-dinitroindazole [Compound No. 28] (8.0 g) was dissolved in ethyl acetate (100 g) and reduced with 10% Pd-C (0.1 g) at ordinary temperature under atmospheric pressure for 8 hours. After completion of the reaction, the reaction mixture was filtered to remove the Pd-C, and the filtrate was concentrated under reduced pressure to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5,6-diaminoindazole (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C:17]3=[N:20][CH:21]=[CH:22][N:16]3[C:15]=2[CH:23]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17]4=[N:20][CH:21]=[CH:22][N:16]4[C:15]=3[CH:23]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)-n1ccnc1CO2
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)-n1ccnc1CO2

Procedure:
In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine to produce 2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-4-pyrimidineamine. 1H NMR (DMSO-d6): 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 8.31 (s, 1H), 7.91 (d, 1H, J=2.3 Hz), 7.74 (d, 1H, J=1.2 Hz), 7.37 (dd, 1H, J=2.3 and 8.8 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=1.2 Hz), 5.29 (s, 2H). LCMS: ret. time: 18.74 min.; purity: 99%; MS (m/e): 318 (MH+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[CH2:1])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
1.75 g (49.0 mmole) of methyltriphenylphosphonium bromide and 5.50 g (49.0 mmole) of potassium t-butoxide were suspended in 200 ml of dried benzene, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. At the end of this time, 8.50 g of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] were dissolved in 40 ml of benzene, and the resulting solution was added to the reaction mixture. The mixture was then stirred for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl ether ranging from 19:1 to 23:2 by volume as the eluent, to give 4.20 g of the title compound as a pale orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[O:3]1.C(O)(=O)C.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][C:5]1[C:6](=[O:7])[C:2]([CH3:16])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CSc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CSc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone (45 mg) in 20 ml carbon tetrachloride, were added acetic acid (0.5 ml) and bromine (0.1 ml). The reaction solution was stirred at room temperature for one hour. Then the reaction was quenched by adding 20 ml of saturated aqueous sodium thiosulfate solution to the reaction solution. After removing the carbon tetrachloride in vacuo, the resulting aqueous layer was extracted with dichloromethane (50 ml×3) and the organic layer was then washed with water (50 ml×1). The organic layer was concentrated in vacuo and the resulting residue was chromatographed (hexane/ethylacetate=2:1) to yield 69 mg of 4-bromo-2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone as a solid. NMR: δ1.52 (s, 6H), 2.55 (s, 3H), 7.33 (d, J=9.3 Hz, 2H), 8.15 (d, J=9.0 Hz, 2H); IR (cm−1): 1704, 1594, 1574, 1486, 1348, 1184, 1069.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(I)c3n2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
A mixture of 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (7.01 g, 16.7 mmol), trimethylsilylacetylene (4.16 mL, 30.0 mmol) and triethylamine (4.66 mL, 33.4 mmol) in N,N-dimethylformamide (18 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (117 mg, 1 mol %), PPh3 (44 mg, 1 mol %) and CuI (10 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (70 mL), dried (MgSO4), evaporated and further purified by column chromatography on silica gel (dischloromethane/heptane 7:3) to give 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (4.73 g, 73%) as an orange solid, which was dissolved in THF (74 mL) and MeOH (56 mL), while stirring at 0° C. potassium carbonate (168 mg, 1.22 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (250 mL) and extracted with TBME (3×250 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from ethyl acetate/hexane to give 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (3.8 g, 72%) as a light brown solid. MS (EI) 317.2 [(M)+]; mp 143° C.