Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([NH2:26])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:13]([F:12])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2F)CC1
Yield: 4.8 %

Procedure:
Following the general procedure for amine displacement using 5,8-dibromoimidazo[1,2-a]pyrazine (0.50 g, 1.81 mmol), 3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamine (0.45 g, 2.17 mmol) and DIPEA (0.47 mL, 2.72 mmol) in iPrOH (5 mL). The crude material is purified by silica gel column chromatography eluting with 90:10 DCM:MeOH to give the title compound (35 mg, 5%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([Si](C)(C)C)[C:5]1=[O:13].[Li+].[CH3:16][CH:17]([N-]C(C)C)[CH3:18].C(Br)C=C>C1COCC1>[CH3:1][CH:2]([CH3:14])[CH2:3][C:4]1([C:17]([CH3:18])=[CH2:16])[CH2:8][CH2:7][NH:6][C:5]1=[O:13]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC1CCN([Si](C)(C)C)C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=C(C)C1(CC(C)C)CCNC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 3-(2-methylpropyl)-1-trimethylsilyl-2-pyrrolidinone (10.2 g, 47.8 mmol) and THF (153 mL) is cooled to -78° C., and LDA (2.0 M, 26.3 mL, 52.6 mmol) is added. The solution is stirred at -78° C. for 30 minutes and then allyl bromide (5.0 mL, 57 mmol) is added. The solution is allowed to warm to 5° C. over 2.5 hours, and is then stirred at 5° C. for 1 hour. After quenching with saturated aqueous ammonium chloride (25 mL), aqueous workup (EtOAc, MgSO4) and purification by column chromatography (1:9:10 v/v CH2Cl2 :EtOAc:hexane) provides 7.76 g (90%) of the title compound as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][NH:14][C:15](=[O:17])[OH:16]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][NH:14][C:15](=[O:16])[OH:17]
Reactant: O=C(O)NCc1cccc(Br)c1
Reactant: OB(O)c1ccco1
Product: O=C(O)NCc1cccc(-c2ccco2)c1

Procedure:
Using the same method as in Example 19-(ii), 2-furanboronic acid was reacted with the (3-bromobenzyl)carbamic acid.tert-butyl to give [3-(furan-2-yl)benzyl]carbamic acid.tert-butyl (yield: 84%).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC=[C:37]([O:41]C)C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:37][O:41][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: COc1cccc(CCBr)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1cccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-bromo-ethyl)-3-methoxy-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][OH:27])[C:23]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:40](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][O:27][CH3:40])[C:23]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4cc(C#N)ccc4n3CCO)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCn1c(COc2ccc(OC3CCN(C(=O)OC(C)(C)C)C3)cc2)nc2cc(C#N)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)-phenoxymethyl]-5-cyano-1-(2-hydroxyethyl)benzimidazole (270 mg) in tetrahydrofuran (5 ml) was added 60% sodium hydride (271 mg) at room temperature, and the mixture was stirred for 30 min. Thereto was added methyl iodide (0.105 ml), and the mixture was stirred for 24 hours. After completion of the reaction, 10% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (199 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:21]=[C:22]([CH:30]([CH3:34])[C:31]([OH:33])=O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[F:27][C:26]([F:29])([F:28])[C:24]1[CH:23]=[C:22]([CH:30]([CH3:34])[C:31]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH3:9])=[O:33])[CH:21]=[C:20]([C:19]([F:18])([F:35])[F:36])[CH:25]=1
Reactant: CNc1ccc(Cl)cc1Sc1ccccc1Cl
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCCl
Product: CC(C(=O)N(C)c1ccc(Cl)cc1Sc1ccccc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
To a solution of 142 mg (0.5 mmol) of 1-chloro-4-methylamino-3-(2-chloro-phenylsulfanyl)-benzene in 2 ml of 1,2-dichloroethane were added 172 mg (0.6 mmol) of 2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid and the reaction mixture was shaken at 80° C. for 1 h. Dicyclohexyl carbodiimide (97 mg, 0.6 mmol) was added and shaking was continued overnight at the same temperature. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel to yield 56 mg (20%) of the title compound as light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(C)(C)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95 %

Procedure:
4-tert-Butyl-2-nitrochlorobenzene (19 g.; 68 mmoles) and morpholine (30 g.; 340 mmoles) were heated at 90° C. for 40 hours. The mixture was then poured into ice water. The yellow solid precipitate was collected by filtration (95% yield) and found to melt at 58°-60° C.
Reaction SMILES: C([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:9]=1[OH:10])(O)=O.NC1C=CC=CC=1.Cl>O>[OH:10][C:9]1[N:8]2[N:11]=[CH:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[C:7]2[N:6]=[CH:5][CH:4]=1
Reactant: CC(C)(c1ccccc1)c1ccc(-c2cnn3c(O)c(C(=O)O)cnc23)cc1
Agent: Cl
Solvent: O
Solvent: Nc1ccccc1
Product: CC(C)(c1ccccc1)c1ccc(-c2cnn3c(O)ccnc23)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To 6-carboxy-7-hydroxy-3-[4-(2-phenylpropan-2-yl)phenyl]pyrazolo[1,5-a]pyrimidine (950 mg) was added aniline (7.0 ml), and the mixture was stirred at 100° C. for 3 hours. To the reaction mixture was added water (20 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with 30% methanol-water to give the title compound (830 mg) at a quantitative yield.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13](O)=[O:14])[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:14]=[C:13]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:12][N:11]1[CH2:10][CH2:9][CH2:8][N:7]2[C:2](=[O:1])[N:3]=[C:4]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=3)[CH:5]=[C:6]12
Reactant: O=C(O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Reactant: C1CCNC1
Product: O=C(CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O)N1CCCC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(6-oxo-8-((3,4,5-trifluorobenzyl)oxy)-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl) acetic acid and pyrrolidine.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14]>C1(C)C=CC=CC=1>[C:1]([O:5][C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CC(=NOC(=O)Cl)c1cccc2ccccc12
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)ON=C(C#N)c1cccc2ccccc12
Reaction time: 3 h

Procedure:
The mixture was stirred for 3 hours at the same temperature and allowed to stand overnight. A solution of tert-butyl alcohol (11.1 g.) and pyridine (12 ml.) in toluene (20 ml.) was added dropwise, under ice-cooling, to the resultant mixture containing 2-chlorocarbonyloxyimino-2-(1-naphthyl)-acetonitrile. The mixture was stirred for 6 hours at the same temperature and allowed to stand overnight. The reaction mixture was then washed with water, 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure and n-hexane and methanol were added to the residue. The mixture was allowed to stand in a refrigerator and the precipitated crystals were collected by filtration and recrystallized twice from methanol to give 2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile (3.3 g.), mp 90° to 92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: Oc1ccc(F)nc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoro-5-hydroxypyridine (6.000 g, 53.05 mmol) in N,N-dimethyl formamide (50 mL) cooled with an ice bath was added NaH (2.80 g, 60%, 70.0 mml) in several potions. After the addition, the mixture was stirred at 0° C. for 10 minutes. 2-iodopropane (6.5 mL, 65.00 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with ether (2×), the combined extracts were washed with 1N NaOH (1×), water (1×), brine (1×), dried over MgSO4 and concentrated to give the product that was used directly without further purification.
Reaction SMILES: O.NN.[N:4]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][N:27]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:22][CH2:21]3)[N:14]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1>CCO>[NH2:27][CH2:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([NH:19][C:15]2[N:14]=[C:13]([N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:6]=[N:5]3)[CH:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Hydrazine monohydrate (0.28 mL, 2.7 eq) was added to a solution of trans-2-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-isoindole-1,3-dione (976 mg, 1 equivalent) in EtOH (60 mL). The reaction mixture was stirred overnight at 70° C., a second aliquot of hydrazine monohydrate (0.22 mL, 2.0 eq) was then added and the mixture was stirred at reflux for 7 hours. The solvent was then evaporated under reduced pressure, the residue was dissolved in a mixture of isopropanol and chloroform and it was acidified until pH 3 by the addition of HCl (1 M). The organic phase was washed 3 times with water. The aqueous phase was basified to pH 8-9 by the addition of NaOH (1 M) and it was extracted 5 times with a mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. This acid/base extraction procedure was repeated 3 times in order to remove phthalazinone. trans-(4-Aminomethyl-cyclohexyl)-(4-benzotriazol-1-yl-pyrimidin-2-yl)-amine was obtained in 71% purity (450 mg, 65% yield). 1H NMR (400 MHz, CD3OD) δ ppm 8.53-8.85 (1 H, bd), 8.40 (1 H, d, J=5.50 Hz), 8.09 (1 H, d, J=8.31 Hz), 7.67 (1 H, m), 7.53 (1 H, m), 7.39 (1 H, d, J=5.50 Hz), 3.76-3.89 (1 H, m), 2.60 (2 H, d, J=6.60 Hz), 2.11-2.28 (2 H, m), 1.88-2.02 (2 H, m), 1.08-1.54 (5 H, m).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].S(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[N:19][C:20]2[N:21]([N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:25]=2)[CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[N:19][C:20]2[N:21]([N:23]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:25]=2[CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])[CH:22]=1
Reactant: Cc1cnc2cc(-c3ccccc3)nn2c1
Reactant: CCCC1CC(=O)N(CO)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(C)cnc23)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (3.18 mmol, 1 eq, 0.5 g) in toluene (20 ml) is added thionyl chloride (3.5 mmol, 1.1 eq, 0.416 g). The mixture is stirred vigorously overnight at 80° C. After this time, 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x122 (3.18 mmol, 1 eq, 0.665 g) and AlCl3 (3.18 mmol, 1 eq, 0.424 g) are successively added. The mixture is stirred at 80° C. for 2 hours. After evaporation of the solvent under reduced pressure, the crude mixture is poured to water and extracted with dichloromethane. The cumulated organic layers are dried over MgSO4, filtered over celite and evaporated under reduced pressure. The crude reaction mixture is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2 (v/v/v)) and crystallized with AcOEt to afford 0.5 g of 1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 202.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[NH2:34]>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[NH:34][C:21]([C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=2[O:4][CH3:3])[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ccc(-c2cccc(C(=O)Cl)c2)c(OC)c1OC
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2cccc(C(=O)Nc3cc([N+](=O)[O-])ccc3Br)c2)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Add a solution of 2′,3′,4′-trimethoxy-biphenyl-3-carbonyl chloride (35) (345 mg, 1.13 mmol) in dichloromethane (5 mL) to an ice cooled solution of 2-bromo-5-nitro-phenylamine (88) (232 mg, 1.07 mmol) in anhydrous dichloromethane (12 mL) and anhydrous pyridine (2.9 mL). Stir the reaction mixture for 15 min at 0° C. and additional 17 h at rt. Pour the reaction mixture into ice cooled 1M aqu. HCl (to get pH ca. 3), extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4 to afford crude 2′,3′,4′-trimethoxy-biphenyl-3-carboxylic acid (2-bromo-5-nitro-phenyl)-amide (89) as a beige solid (542 mg, quant.). 1H NMR (400 MHz, CDCl3): 3.72 (s, 3H); 3.91 (s, 3H); 3.93 (s, 3H); 6.77 (d, 1H, J=8.6 Hz); 7.08 (d, 1H, J=8.6 Hz); 7.56 (t, 1H, J=8.8 Hz); 7.75 (d, 2H, J=8.8 Hz); 7.86 (d, 1H, J=8.8 Hz), 7.87 (d, 1H, J=8.8 Hz); 8.09 (t, 1H, J=1.7 Hz); 8.61 (br. s, 1H); 9.59 (d, 1H, J=2.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[C:17]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:18]=[C:19]([C:24](OC)=[O:25])[CH:20]=2)[CH2:15]1>ClCCCl.C(Cl)Cl>[CH3:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[C:17]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[CH:18]=[C:19]([C:24]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:25])[CH:20]=2)[CH2:15]1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(C)C2
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)C(=O)N(C)C3)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 5-methyl-2-aminopyridine (144 mg, 1.33 mmol) in DCE at 0° C. was added Al(CH3)2Cl drop-wise. The reaction was stirred at room temperature for 20 minutes followed by the addition of methyl 2-methyl-7-(4-(methylsulfonyl)phenoxy)-3-oxoisoindoline-5-carboxylate. After stirring the reaction at room temperature for 14 hours, it was diluted with CH2Cl2 and quench with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL) slowly. The solution was washed with brine, dried over Na2SO4, and concentrated. The crude sample was introduced into a silica gel column and eluted with 5-10% MeOH/CHCl3 to provide the product (40 mg, 85% yield) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3 H) 3.10 (s, 3 H) 3.19-3.33 (m, 3 H) 4.40 (s, 2 H) 7.19 (d, J=8.67 Hz, 2 H) 7.53-7.66 (m, 1 H) 7.82 (s, 1 H) 7.97 (d, J=8.67 Hz, 2 H) 8.10-8.17 (m, 1 H) 8.19 (s, 2 H) 8.81 (s, 1 H); LC-MS (ESI)+ m/z=452.00 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:9]=[C:10]([CH:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[OH:16])[CH:11]=[C:12]([F:14])[CH:13]=1>C(Cl)Cl>[F:7][C:8]1[CH:9]=[C:10]([C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:16])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: OC(c1cc(F)cc(F)c1)c1nccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1cc(F)cc(F)c1)c1nccs1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of CrO3 (1.1 g, 11 mmol) in CH2Cl2 at r.t. was added pyridine (1.8 mL, 22 mmol) and the resulting mixture was stirred for 20 min.. The alcohol from Step 1 in CH2Cl2 was added and the resulting mixture was stirred for 16 h. Then ET2O was added and the resulting mixture was filtered through silica gel and washed with Et2O. After evaporation the residue was chromatographed on silica gel eluting with 7:3 mixture of hexane:EtOAc to give 1.66 g (90%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[I-:12].[Na+].O>CC(C)=O>[I:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CI)cc1
Yield: 95 %

Procedure:
A suspension of 1-chloromethyl-4-nitro-benzene (10 g, 58.3 mmol) and sodium iodide in acetone (150 ml) was refluxed for 1 h. Water was added until complete dissolution and the mixture extracted with ethyl acetate (4×100 ml). The combined organic layers were extracted with brine, dried over sodium sulfate and concentrated in vacuo yielding 13.9 g (95%) 1-Iodomethyl-4-nitro-benzene as beige crystals.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9].CS(O[CH2:25][CH2:26][C:27]([CH3:31])=[C:28]([F:30])[F:29])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH2:6]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:25][CH2:26][C:27]([CH3:31])=[C:28]([F:30])[F:29])=[O:16])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: CCCCOc1ccc(C(=O)O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)OCCC(C)=C(F)F)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.39 g (2.0 mmol) of 6-butoxynicotinic acid, synthesized by a method in accordance with one used in Intermediate Production Example 1, and 0.40 g (2.0 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.34 g (4.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 0.45 g (yield: 75%) of 4,4-difluoro-3-methyl-3-butenyl 6-butoxynicotinate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16].P(Cl)(Cl)([Cl:33])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([Cl:33])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(O)n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
Into a solution of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4,6-dihydroxypyrimidin-2-yl]piperidine-1-carboxylate (45 g, 105.02 mmol, 1.00 equiv) in toluene (500 ml) was added phosphoryl trichloride (16.1 g, 105.00 mmol, 1.00 equiv) and N,N-Diisopropylethylamine (27 g, 209.30 mmol, 1.99 equiv). The resulting solution was stirred for 20 mins at 120° C. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate/petroleum ether (1:10) to give 30 g of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate as a light yellow solid. MS m/z [M+H]+ (ESI): 447.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[OH:8])[CH2:2][CH2:3][CH3:4].[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([CH:7]([O:8][C:14](=[O:15])[CH2:13][C:11]#[N:12])[CH3:9])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: N#CCC(=O)O
Reactant: CCCCOC(=O)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)C(C)OC(=O)CC#N

Procedure:
A mixture of 292.32 g of butyllactate, 204.14 g of cyanoacetic acid, and 14.66 g of 4-dimethylaminopyridine (DMAP) in 2000 ml of CH2Cl2 was stirred in a 3 L three-neck round bottom flask equipped with a mechanical stirrer. About 50 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (495.19 g in 500 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.