Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][S:6][CH2:7][C:8]1[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[C:2]=[S:3].[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1>C(#N)C>[CH3:15][N:14]([CH2:13][C:11]1[O:12][C:8]([CH2:7][S:6][CH2:5][CH2:4][NH:1][C:2]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)=[S:3])=[CH:9][CH:10]=1)[CH3:16]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CN(C)Cc1ccc(CSCCN=C=S)o1
Solvent: CC#N
Product: CN(C)Cc1cccc(OCCCNC(=S)NCCSCc2ccc(CN(C)C)o2)c1
Yield: 89.6 %

Procedure:
To a solution of 5-[[[2-(isothiocyanato)ethyl]thio]methyl]-N,N-dimethyl-2-furanmethanamine (0.77 g) in dry acetonitrile (3 ml) was added a solution of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (0.63 g) in dry acetonitrile (3 ml). After 1 hour the solution was evaporated to dryness to give an oil which was chromatographed (silica/methanol-0.88 ammonia 79:1). The appropriate eluate was evaporated to dryness to give the title compound (1.25 g) as an oil.
Reaction SMILES: Br[C:2]([F:20])([F:19])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH:7]1[C:15]([O:17][CH3:18])=[O:16])([F:5])[F:4].C(=O)(O)[O-].[Na+:25].[S:26](S([O-])=O)([O-:28])=[O:27].[Na+].[Na+].C(#N)C>O>[CH3:18][O:17][C:15]([CH:7]1[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:6]1[C:3]([F:5])([F:4])[C:2]([F:20])([F:19])[S:26]([O-:28])=[O:27])=[O:16].[Na+:25]
Reactant: O=S([O-])S(=O)[O-]
Reactant: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)Br)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)[O-])C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a glass flask equipped with a thermometer and a capacitor were charged 2.00 g (5.49 mmol) of dimethyl 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylate, 0.920 g (11.0 mmol) of sodium bicarbonate, 1.62 g (9.30 mmol) of sodium dithionite, 15 mL of acetonitrile and 15 mL of water, and the mixture was stirred at 50° C. for 8 hrs. The disappearance of the raw material was confirmed by 19F-NMR to decide completion of the reaction. Thereafter, acetonitrile was distilled off in vacuo to obtain an aqueous solution of crude sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfinate (precursor compound (a-4)) represented by the following formula (a-4) without carrying out further purification, which was used for the following reaction.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][N:20]1[CH2:24][CH2:23][C@@:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH2:25][C:26]#[CH:27])[C:21]1=[O:36].N(CC)CC>C1COCC1.[Cu](I)I>[CH3:19][N:20]1[CH2:24][CH2:23][C@@:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])([CH2:25][C:26]#[C:27][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[C:21]1=[O:36]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
Copper Iodide (149.46 mg, 0.7800 mmol), followed by PdCl2(Ph3P)2 (275.41 mg, 0.3900 mmol) was added portionwise to a solution of 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (4 g, 10.99 mmol) (which may be prepared as described in Description 12), tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (1.98 g, 7.85 mmol) (which may be prepared as described in Description 4) and Et2NH (4.06 mL, 39.24 mmol) in THF (50 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was suspended in EtOAc and washed with water/sat. aq. NaHCO3. The organics were collected, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with a 100 g SNAP cartridge, eluting with 50 to 100% EtOAc/i-hexane to afford tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (D13a) (4.09 g, 8.3726 mmol) as a pale yellow foam. The NMR was the same as that for the R isomer produced in Description 13 but also contained traces of ethyl acetate and impurities.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]1(B(O)O)[C:29]2[C:30]3=[C:31]4[C:26](=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]4[CH:21]=[CH:20][C:19]3=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2[C:22]3[C:31]4=[C:30]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:29]5[CH:28]=[CH:27][C:26]4=[CH:25][CH:24]=2)=[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1
Reactant: COc1ccc(Br)c(-c2ccccc2)c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)c(-c2ccccc2)c1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 11.1 g (42.4 mmol) of 2-bromo-5-methoxybiphenyl, 10.43 g (42.4 mmol) of pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 12.4 g (76%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>>[CH3:9][C:10]1[C:11]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:4]4[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: CC1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 31.3 %

Procedure:
Using 4-methylisothiazolidine 1,1-dioxide (270 mg) described in Preparation Example 9 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 4, the title compound (134 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:32][CH:31]([CH2:33][CH2:34]O)[CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:34][CH2:33][CH:31]3[CH2:32][O:29][CH2:30]3)=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: OCCC1COC1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3COC3)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Reaction time: 2.5 h
Yield: 53.8 %

Procedure:
To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2. found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CN([CH:9]=[C:10]1[C:15](=[O:16])[O:14][C:13]([CH3:18])([CH3:17])[O:12][C:11]1=[O:19])C>O1CCCC1>[CH:1]1([CH:9]=[C:10]2[C:11](=[O:19])[O:12][C:13]([CH3:17])([CH3:18])[O:14][C:15]2=[O:16])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CN(C)C=C1C(=O)OC(C)(C)OC1=O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(=CC2CC2)C(=O)O1
Reaction time: 1 h
Yield: 51 %

Procedure:
A 0.5 M solution (13 ml, 6.6 mmol) of cyclopropylmagnesiumbromide in tetrahydrofuran was added dropwise to a solution of 5-dimethylaminomethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g, 5.0 mmol) in tetrahydrofuran (12 ml) at 23° C. After stirring the mixture for 1 hr, the reaction solution was quenched with saturated aqueous ammonium chloride solution. The organic layer was separated and the water layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 5:1) followed by crystallization from hexane to give 498 mg of the pure title product as a pale yellow powder. (yield: 51%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][C:11](=O)/[C:10]/2=[CH:15]\[N:16](C)C)[CH:5]=[CH:6][C:7]=1[F:8].O.[NH2:20]N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[CH:15]=[N:16][NH:20][C:11]=3[CH2:12][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NN
Reactant: CN(C)/C=C1\C(=O)CCC1c1ccc(F)c(F)c1
Solvent: CCO
Solvent: O
Product: Fc1ccc(C2CCc3[nH]ncc32)cc1F
Temperature: 80 °C
Yield: 28 %

Procedure:
To the mixture of (+/−)-(2Z)-3-(3,4-difluorophenyl)-2-((dimethylamino)methylene)cyclopentanone (8.5 g, 34 mmol) in ethanol (200 mL), is added hydrazine hydrate (15 mL) and the mixture is heated to 80° C., overnight. The mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by preparative HPLC using a CXTH instrument with a DAISO 10 μC18 250×50 mm column, a 9 mL injection, a flow rate of 70 mL/min, a wavelength of 214 nm and a mobile phase of 10-80% acetonitrile in 0.1% TFA/H2O to give the title compound as a white solid (2.1 g, 28%). ES/MS m/z 221 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:27])=[O:26]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (149 mg, 0.322 mmol) in 5 mL of dichloromethane at 0° C. was added triethylamine (0.050 mL, 0.39 mmol), followed by morpholine (0.040 mL, 0.48 mmol). After four hours, the mixture was concentrated in vacuo to give the crude titled product. ESI+MS: 513.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:44])(=[N:29]C(C3CCCN3C(OC(C)(C)C)=O)=O)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.S(=O)(=O)(O)O>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:44])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)N=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-(1-tert-butoxycarbonyl-pyrrolidin-2-carbonyl)sulfoximide (1.2 g, 0.00182 mol, nonpolar isomer) in methanol (4 mL) was added conc. sulfuric acid (0.7 g, 0.00728 mol) at 5-10° C. The reaction mixture was stirred at 25-30° C. for 4 hr and then diluted with water. Product obtained was extracted in chloroform at 8-9 pH. Organic layer was dried and concentrated to give 640 mg of titled product in 63% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)C=Cc1ccc(F)cc1O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cc(F)ccc1C=CC(=O)OC

Procedure:
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (106 mg) was reacted with K2CO3 (125 mg) and butyl iodide (0.1 ml) at 80° C. for 3 hrs as described above to yield title compound (121 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])[CH:2]([CH3:4])[CH3:3].B(F)(F)F.[CH3:17][CH2:18][O:19]CC.C(O)(=O)C.CC([O-])=O.[Na+]>>[OH:11][C:8]1[CH:7]=[C:6]([OH:12])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=1[C:18](=[O:19])[CH3:17]
Reactant: CCOCC
Reactant: CC(C)Cc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(CC(C)C)c(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Isobutyl-benzene-1,3-diol (1 eq) was taken up in BF3.OEt2 (6 eq) and acetic acid (2 eq) was added. The solution was heated for 16 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted twice with diethyl ether. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-(2,4-dihydroxy-5-isobutyl-phenyl)-ethanone, which was used without additional purification.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH:17]1([OH:23])[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29](O)[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1.C(Cl)Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[C:27]([CH:26]=1)[O:22][CH:19]1[CH2:20][CH2:21][CH:17]([OH:23])[CH2:18]1
Reactant: OC1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC(O)C1
Temperature: 25 °C

Procedure:
Di-tert-butyl azodicarboxylate was added at 0° C. to a mixture of 1,3-cyclopentandiol (1.02 g), 5-fluoro-2-nitrophenol (0.79 g) and triphenylphosphine (1.97 g) in THF (15.0 ml). After stirring at room temperature over weekend the mixture was treated with 2 M aq. HCl (20.0 ml) and refluxed for 30 min. The reaction mixture was diluted with methylene chloride. The layers were separated. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The crude was purified by chromatography to yield the desired product.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:7][CH2:6][CH2:5][N:4]([CH:8]([CH3:10])[CH3:9])[CH:1]([CH3:3])[CH3:2])[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CC(C)N(CCN)C(C)C
Product: CC(C)N(CCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1)C(C)C

Procedure:
Using 2-(diisopropylamino)-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH3:33][S:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:37]3[CH:38]=[CH:39][N:40]=[C:35]([S:34][CH3:33])[N:36]=3)[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:9]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: CSc1nccc(Cl)n1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
2.6 g (6 mmol) of 1-(4-methoxybenzyl)-3-(3-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were dissolved in a mixture of 520 ml of dioxane and 130 ml of water under a nitrogen atmosphere. 709 μl (6 mmol) of 2-methylthio-4-chloro-pyrimidine, 3.9 g (12 mmol) of cesium carbonate and 650 mg (0.6 mmol) of palladium tetrakis were added consecutively to the resulting solution under stirring. The reaction mixture was heated at 100° C. for 6 hours, then filtered through a celite pad and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and evaporated to dryness. The crude was finally purified by flash-chromatography on a silica gel column (cyclohexane-ethylacetate; from 9/1 to 4/1), giving 2.3 g (88%) of the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]1=[O:35]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:30]1[C:29](=[O:35])[N:28]([CH3:27])[CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccn(C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1cccc(CBr)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
N-Bromosuccinimide (2.17 g, 12.2 mmol) and benzoic peroxyanhydride (0.295 g, 1.22 mmol) were added to a flask containing a solution of 1,3-dimethylpyridin-2(1H)-one (1.50 g, 12.2 mmol) in carbon tetrachloride (250 mL, degassed with flowing N2 for 5 minutes). The mixture was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, filtered through filter paper, and the filtrate was concentrated under vacuum. The residue was suspended in diethyl ether (20 mL), stirred for 15 minutes, and the liquid was decanted. The solids were rinsed with diethyl ether (3×5 mL), then dried under vacuum to give 3-(bromomethyl)-1-methylpyridin-2(1H)-one as a yellow solid (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)C(=CNc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(C)c(C)c1
Yield: 16.6 %

Procedure:
Compound 2c was prepared following the procedure described in Step 2 of Example 1 using 598 mg (2.41 mmol) of the crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a and 427 mg (2.65 mmol) of 4-trifluoromethyl-phenylamine. The product 2c was purified by flash chromatography (0-40% ethyl acetate in hexane) to yield 151 mg of 2-(3,4-dimethyl-benzoyl)-3-(4-trifluoromethyl-phenylamino)-acrylic acid methyl ester as a yellow crystalline solid: LC-MSD, m/z for C20H18F3NO3 [M+H]+=378.5; HPLC retention time: 3.0 min.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[OH:21]>CN(C)C=O.O.Cl[Cu]>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cc(F)ccc1F
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(F)ccc2F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
Into a 500 mL 3-necked round-bottom flask, was placed a solution of sodium hydride (3.9 g, 162.50 mmol, 1.7 equiv) in N,N-dimethylformamide (200 mL). This was followed by the addition of a solution of 1-fluoro-4-nitrobenzene (13.6 g, 96.39 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 0° C. over 20 min. The reaction mixture was stirred for 2 hr at 25° C. and then CuCl (9.6 g, 96.97 mmol, 1.0 equiv) was added, followed by addition of a solution of 2,5-difluorophenol (15.5 g, 119.15 mmol, 1.2 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath and then diluted with water and washed with ether, water and brine. The reaction mixture was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 19.5 g (81%) of 1,4-difluoro-2-(4-nitrophenoxy)benzene as a brown solid,