Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][C:6]=1[O:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]2[O:20][CH2:21][O:22][C:16]=2[CH:15]=1)[C:9]([O:11]CC)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].[NH4+].[OH-].Cl>CO.C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][C:6]=1[O:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]2[O:20][CH2:21][O:22][C:16]=2[CH:15]=1)[C:9]([OH:11])=[O:10])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(Oc1ccc(C(=O)OC)cc1CC(C)C)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(OC(C(=O)O)c2ccc3c(c2)OCO3)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.518 g (3.66 mmol) of the product of Step A dissolved in 8.0 mL of methanol was added 1.0 mL of a 5.0M solution of aqueous sodium hydroxide. The reaction was stirred at room temperature and monitored by TLC (80:15:1 CHCl3 --MeOH--NH4OH). After 1.5 hours the reaction was judged to be complete and the reaction mixture was adjusted to pH=5 with 1.0N HCl. The reaction mixture was then partitioned between EtOAc and water, separated, dried (MgSO4), filtered, and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (80:15:1); evaporation of the purified fractions and drying in vacuo afforded the title compound as an amorphous foam.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[F:23][C:24]1[C:25]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:26]([CH:30]=[C:31]([CH:34]=O)[C:32]=1[F:33])[C:27]([OH:29])=[O:28]>C(#N)C>[C:4]([O:3][C:1]([NH:2][CH2:34][C:31]1[C:32]([F:33])=[C:24]([F:23])[C:25]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28])=[O:8])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=Cc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CC(C)(C)OC(N)=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)O)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
tert-Butyl carbamate (commercially available, 187 mg, 1.602 mmol), trifluoroacetic acid (123 μL, 1.602 mmol), and triethylsilane (255 μL, 1.602 mmol) were added sequentially to a suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid (225 mg, 0.534 mmol) obtained in Step A of Example 5 in acetonitrile (anhydrous, 20 mL). The mixture was stirred at room temperature for 5 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 5-(tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid. [LC/MS m/z 523 (M+1)]. Then, trifluoroacetic acid (0.5 mL) was added to a solution of the resultant product in methylene chloride (20 mL), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was recrystallized from a mixed solvent of diethyl ether:hexane (1:1) to give 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid trifluoroacetate (285 mg, 99% in 2 steps) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.[Cl-].[NH4+].[CH3:23][N:24]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:23]([C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1)#[N:24]
Reactant: CN1CCCC1=O
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: CCSc1ccccc1-c1nc2cc(C#N)cnc2n1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of zinc cyanide (0.47 g), tetrakis(triphenylphosphine)palladium (0.12 g), 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.70 g), and N-methylpyrrolidone (hereinafter referred to as NMP) (4 ml) was stirred at 90° C. for 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.59 g of 6-cyano-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 48).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:88])[C@@H:65]([NH2:87])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:88])[C@@H:65]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 195 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 108 mg HOBt, 135 mg EDC and 0.2 ml DIPEA. After 20 minutes 255 mg 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product thus obtained was pure enough for the following transformation. Yield: 400 mg.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[C:21]1[N:26]=[C:25]([CH3:27])[N:24]([CH2:28][CH3:29])[C:23](=[O:30])[C:22]=1[CH3:31].O>O1CCOCC1>[CH3:27][C:25]1[N:24]([CH2:28][CH3:29])[C:23](=[O:30])[C:22]([CH3:31])=[C:21]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH2:8][C:7]3[CH:18]=[CH:19][C:4]([F:3])=[CH:5][CH:6]=3)=[CH:11][CH:12]=2)[N:26]=1
Reactant: OCc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCn1c(C)nc(Cl)c(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(C)nc(OCc2ccc(OCc3ccc(F)cc3)cc2)c(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Sodium hydride (55% in mineral oil) (0.23 g) was suspended in 10 ml of dioxane, and then 1.24 g of 4-(4'-fluorobenzyloxy)benzyl alcohol was added thereto. The resulting mixture was stirred for one hour at room temperature, then incorporated with 1.00 g of 6-chloro-2,5-dimethyl-3-ethyl-4(3H)-pyrimidinone and stirred for 15 hours. The resulting solution was poured into water, and the resulting crystals were filtered off and recrystallized from a benzene-hexane mixture to give 1.83 g of the intended product.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[Br:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24](OC)=[O:25])[CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[Br:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:24]\[OH:25])/[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1COc1cccc(Br)n1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Br)n1
Yield: 97.9 %

Procedure:
Sodium methoxide (0.34 g, 6.0 mmol) and methyl formate (1 ml, 16 mmol) were added portionwise to a stirred solution of methyl 2-(6-bromopyrid-2-yloxymethyl)phenylacetate (0.8 g, 2.3 mmol) in dry toluene (10 ml) under a nitrogen atmosphere at room temperature. After 8 hours at room temperature the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and the ethyl acetate removed to give (E)-methyl 2-[2-(6-bromopyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (0.82 g, 80%) as a brown gum which was used in the final stage without further purification; 1H NMR (270 MHz)δ: 3.74(3H,s), 5.28(2H,s), 6.66(1H,d), 7.06(1H,d), 7.15-7.55(6H,m), 11.95(1H,d) ppm.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH:11]=[CH:10]1)(C(C)(C)C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.C1COCC1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C1COCC1>[Cl:24][C:19]1[C:18]2[C:17]3[C:16](=[C:27]([CH3:28])[O:26][N:25]=3)[C:15](=[O:29])[N:14]([CH:12]3[CH2:13][CH:9]([OH:8])[CH:10]=[CH:11]3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(C1C=CC(O)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
To a stirred solution of 5-[4-(t-butyl-dimethylsilanyl-oxy)cyclopent-2-en-1-yl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (3.4 g, 7.9 mmol) in THF (60 mL) was added HF pyridine/pyridine/THF (1:2:8; 50 mL). The mixture was stirred at r.t. for 6 hours. Solid NaHCO3 (6 g) and ethyl acetate (60 mL) were added. Aqueous NaHCO3 was then added until the reaction was quenched The layers were separated and the organic fraction was washed (brine, water, aqueous CuSO4), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave desired product (2.2 g, 88%). 1H NMR (CDCl3, 400 MHz) δ; 7.59 (d, 1H); 7.37 (t, 1H); 7.30 (d, 1H); 6.15 (m, 1H); 5.91 (m, 1H); 5.78 (broad, 1H); 4.82 (broad, 1H); 2.81 (s, 3H); 2.82 (m, 1H); 2.18 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:32]3\[C:33](=[O:39])[NH:34][C:35]4[C:31]\3=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=3[F:22])[CH:38]=[CH:37][CH:36]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(-c5cccc(F)c5F)c43)c(C)c2C1=O
Yield: 61.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 6 (43 mg, yield 61.4%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.S(=O)(=O)(O)O>COCCOC.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.CO>[NH2:1][C:2]1[C:3]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:4][C:5]([Br:9])=[CH:6][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: Nc1c(-c2ccccc2)cc(Br)cc1S(=O)(=O)O
Temperature: 0 °C

Procedure:
To a mixture of 37.8 g (100 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 32 g (300 mmol) of sodium carbonate in 300 ml of 1,2-dimethoxyethane and 150 ml of water are successively added, under a nitrogen atmosphere, 5.8 g (5 mmol) of tetrakis(triphenylphosphine)palladium (0) and 19.5 g (160 mmol) of benzeneboronic acid. The mixture is heated at the reflux temperature for 4 hours and the reaction medium is then concentrated under reduced pressure. The residue thus obtained is then dissolved in a mixture containing 300 ml of methanol, 300 ml of 0.1N hydrochloric acid and 16 ml of 95% sulphuric acid. The mixture is concentrated to 100 ml under reduced pressure, cooled to 0° C. and filtered. The residue is purified by chromatography on an RP 18 reverse-phase column, eluting with an acetonitrile:water mixture (2:8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:17])=[CH:10][CH:11]=1)#[CH:18]
Reactant: O=Cc1ccc(C(O)c2ccc(F)cc2)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of the product of Step B (0.21 g, 0.91 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.21 g, 1.1 mmol) and K2CO3 (0.152 g, 1.1 mmol) in anhydrous MeOH (5 ml) was stirred for overnight at room temperature. The solvent was distilled off and the residue was taken in EtOAc (50 ml), washed with H2O and dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the crude product (0.195 g; 95%), which was used in the next step without purification. 1H-NMR (CDCl3) 3.05 (s, 1H); 5.76 (s, 1H); 7.0 (tr, 2H, J=8.58 Hz); 7.25-7.33 (m, 4H); 7.44 (d, 2H, J=8.29 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:24])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)phenyl)acetate (Step B, 4 g, 13.6 mmol) in dry THF (30 ml) at −68° C. under a dry argon atmosphere was added LiHMDS drop wise (1 M solution in THF, 17.45 ml, 17.4 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3I (5.71 g, 40.26 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for another 15 hours. The reaction was quenched with ice, and the product was extracted with EtOAc (2×), the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether, 5:1) to give the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[CH:13]=2)=[CH:8][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[CH:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:7][CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
tert-butyl (3-(4-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (100 mg, 0.14 mmol) was stirred in TFA/DCM (1:1) solution (2 mL) for 15 mins. The solution was concentrated under vacuum to give N-(3-amino-2,2-dimethylpropyl)-4-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamide which was carried to the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.O>C1(C)C=CC=CC=1>[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[CH3:1][O:2][CH:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][OH:8]
Reactant: COCCOCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(O)COCCO

Procedure:
682 grams Methyl Carbitol (diethylene glycol monomethyl ether, Union Carbide) were azeotropically esterified with 598.9 grams acrylic acid in 272 grams toluene in the presence of 22.8 grams p-toluenesulfonic acid and inhibitors until no more water was collected. Conditions were 95°-98° C., nitrogen sparge in vacuo. On completion, the product was washed and neutralized with sodium carbonate. 1,300 ppm p-methoxyphenol were added and solvent removed at 80° C. at maximum vacuum with an air sparge. Filter aid was added and the product filtered to clarity at 50° C. The final product was a clear, light yellow liquid, viscosity 6 cps with a Gardner 1 color.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH:10]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[C:17]1[C:18]2[C:23]([CH:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2>[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(OCC)C>[CH:10]1([O:15][C:17]2[C:30]3[C:25]([CH:24]=[C:23]4[C:18]=2[CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OC1CCCC1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(OC3CCCC3)c3ccccc3cc2c1
Temperature: 100 °C
Yield: 68.6 %

Procedure:
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under vacuum and back-filled with argon. To this was added toluene (2 mL) and cyclopentanol (109 μL, 0.90 mmol). The mixture was heated at 70° C. for 15 min at which time 9-bromoanthracene (193 μL, 0.75 mmol), Pd2 (dba)3 (10.3 mg, 0.0113 mmol), (R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of toluene were added. The mixture was heated at 100° C. under an atmosphere of argon. After 20 hours diethyl ether (30 mL) and brine (30 mL) were added. The organic layer was separated and dried over anhydrous MgSO4. The drying agent was removed by filtration and the mother liquor concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (99:1 hexanes:ethyl acetate) to afford 9-anthryl cyclopentyl ether (135 mg, 68% yield) as a yellow solid
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH2:7][CH2:6][CH2:5]2.[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:27][C:26]=1[Cl:36]>N1C=CC=CC=1>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][S:32]([C:28]4[CH:29]=[C:30]([Cl:31])[C:25]([NH2:24])=[C:26]([Cl:36])[CH:27]=4)(=[O:34])=[O:33])=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:23])=[CH:20][CH:19]=1)#[N:22]
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(N)ccc32)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(NS(=O)(=O)c4cc(Cl)c(N)c(Cl)c4)ccc32)cc1

Procedure:
1.0 g 6-amino-1-[3-(4-cyano-phenyl)propionyl]-1,2,3,4-tetrahydro-quinoline (see Example, 5) are dissolved in 8 ml of pyridine, combined with 1 g of 4-amino-3,5-dichloro-phenylsulphonic acid chloride in batches and then heated for 40 minutes to 100° C. Then the solvent is eliminated, the residue is triturated with 1N hydrochloric acid and extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Mg]Br.C(OCC)C.O.Cl>C(OCC)C>[F:11][C:10]1[C:2]([CH3:14])=[C:3]([C:7]([F:13])=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1c(F)c(F)cc(F)c1C(=O)O
Temperature: -10 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
200 mg of 2,3,4,6-tetrafluorobenzoic acid was dissolved in 10 ml of diethyl ether and cooled to −10° C. in an argon atmosphere. Then 1.72 ml of a methyl magnesium bromide-diethyl ether solution (3 moles/liter) was added dropwise. After completion of dropwise addition, the reaction mixture was heated to room temperature and stirred at room temperature for 17 hours. The reaction mixture was added to about 50 ml of cold water and adjusted to pH 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate and separated into liquids. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give 181 mg of 3,4,6-trifluoro-2-methylbenzoic acid (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:15]([OH:17])[CH3:16]>C1COCC1>[CH2:15]([O:17][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([F:11])=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F

Procedure:
Prepared analogously to example 156a from 2,4-difluoro-5-nitro-benzoyl chloride and ethanol with TEA in THF.