Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[S:26]([CH2:37][CH2:38][NH:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43]Cl)[S:27][CH2:28][CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][Cl:35].C[C:47]([CH3:49])=[O:48]>C(#N)C>[Cl-:35].[Cl-:35].[S:26]([CH2:37][CH2:38][NH:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:49][CH2:47][OH:48])[CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1)[S:27][CH2:28][CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]=[N:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: O=C(CCCCl)NCCSSCCNC(=O)CCCCl
Reactant: CC(C)=O
Reactant: OCCN(CCO)c1ccc(N=Nc2ccnc3ccccc23)cc1
Solvent: CC#N
Product: O=C(CCC[n+]1ccc(N=Nc2ccc(N(CCO)CCO)cc2)c2ccccc21)NCCSSCCNC(=O)CCC[n+]1ccc(N=Nc2ccc(N(CCO)CCO)cc2)c2ccccc21
Product: [Cl-]

Procedure:
0.35 g of 2,2′-({4-[(quinolin-4-yl)diazenyl]-phenyl}-imino)diethanol and 0.18 g of N,N′-(disulfanediyldiethane-2,1-diyl)bis(4-chlorobutanamide) are solubilized in 2 mL acetonitrile. The mixtured is heated at reflux for 24 h, cooled and poured on 50 mL acetone. The resulting oil is washed several times with acetone.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][Cl:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:38].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc2nc(NCc3ccccc3)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCc2ccccc2)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (70 mg, 0.30 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-benzyl-3-(chloromethyl)-6-methoxyquinolin-2-amine hydrochloride SLA 41008 (105 mg, 0.30 mmol) followed by a 2 N aq. LiOH (0.30 mL, 0.60 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 17.3 mg of 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 44 as a yellow solid (16 mg, 9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)=[O:9])=[C:4]([O:17][CH3:18])[C:3]=1[F:19].C(=O)([O-])[O-:21].[Cs+].[Cs+].[CH2:26](O)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]([CH2:12][O:11][CH2:26][CH3:27])([OH:21])[C:13]([F:14])([F:15])[F:16])=[C:4]([O:17][CH3:18])[C:3]=1[F:19]
Reactant: COc1c(C(=O)C2(C(F)(F)F)CO2)ccc(Cl)c1F
Reactant: CCO
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOCC(O)(C(=O)c1ccc(Cl)c(F)c1OC)C(F)(F)F

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)-oxiranyl]methanone obtained in example 12 are stirred with 622 mg (1.9 mmol) Caesium carbonate in 8 ml ethanol. The reaction is quenched by addition of water after 1 day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 173 mg 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxy propan-1-one. 1H-NMR (CDCl3); δ=1.20 (t, 3H), 3.60 (dq, 1H), 3.62 (dq, 1H), 3.79 (d, 1H), 3.97 (d, 3H), 4.09 (d, 1H), 4.72 (s, 1H), 7.11 (dd, 1H), 7.18 (dd, 1H). To 26 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxy propan-1-one in 0.44 ml toluene and 0.13 ml 1,4-dioxane are added 30 μl acetic acid and 0.11 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethylacetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxypropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.7 ml methanol is cooled to 5° C. and 180 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride 30%) yields 3.2 mg of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.O[C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:19]([CH3:21])([CH3:20])[O:18][B:17]([OH:22])[C:16]=2[CH:23]=1)([CH3:11])[CH3:10].[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)(Cl)Cl>[N:24]([C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:19]([CH3:21])([CH3:20])[O:18][B:17]([OH:22])[C:16]=2[CH:23]=1)([CH3:11])[CH3:10])=[N+:25]=[N-:26]
Reactant: CC(C)(O)c1ccc2c(c1)B(O)OC2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
A solution of TFA (200 μL, 2 mmol) in chloroform (3 mL) was added slowly to a mixture of 6-(2-hydroxypropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (88 mg, 0.4 mmol) and sodium azide (80 mg, 1.2 mmol) in chloroform (7 mL) at −5° C. to 0° C. The cooling bath was removed and the mixture was stirred at rt overnight. Concentrated ammonium hydroxide was added until pH was basic (moist PH paper). DCM (50 mL) was added and the organic layer was washed with brine:water (1:1), dried over Na2SO4, filtered and concentrated to give the crude product 6-(2-azidopropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (100 mg) as colorless oil. It was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][Si:8]([C:11]#[CH:12])([CH3:10])[CH3:9]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:7][Si:8]([CH3:10])([CH3:9])[C:11]#[C:12][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
Under a nitrogen atmosphere a solution of 12.0 grams (0.074 mole) of 2-bromothiophene, 9.0 grams (0.092 mole) of trimethylsilylacetylene, and 120 ml of triethylamine was stirred, and 0.52 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride and 0.28 gram (catalyst) of copper(I) iodide were added. Upon completion of addition, the reaction mixture was stirred at ambient temperature during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether, and the solution was washed with two portions of an aqueous 10% ammonium chloride solution, one portion of water, and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 11.0 grams of 2-trimethylsilylethynylthiophene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:17]I.[H-].[Na+]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17]
Reactant: CI
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Product: Cl

Procedure:
Alkylation of 2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)acetophenone (8.64 g) with methyl iodide (5.27 g) in the presence of sodium hydride (as a 50% dispersion in oil, total weight of dispersion 1.78 g) in tetrahydrofuran (150 ml) at 0° over 2 hours, yielded the title compound which was isolated as a hydrochloride salt, m.p. 125°-129°, 3.17 g (yield 34.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:26]3[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=3)=[CH:14][C:6]1=2
Reactant: COc1ncc(B(O)O)cn1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: COc1ncc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)cn1
Yield: 42 %

Procedure:
1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (500 mg) was reacted with 2-methoxypyrimidine-5-boronic acid as in General Procedure 4A to give the title compound as a pale orange foam in 42% yield. M.p. (foam), LCMS: m/z=404.36 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.51 (t, J=5.3 Hz, 2H), 3.66-3.70 (m, 2H), 4.01 (s, 3H), 4.49 (s, 2H), 4.99 (bs, 1H), 6.46 (d, J=1.5 Hz, 1H), 7.18-7.26 (m, 2H), 7.35 (d, J=8.3 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 8.50 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH:9]([O:12][C:13]1[CH:18]=CC=C[CH:14]=1)[CH:10]=[CH2:11]>CO>[OH:7][CH2:8][CH:9]([O:12][C:13]([CH3:14])([CH3:18])[CH3:1])[CH:10]=[CH2:11]
Reactant: O=C([O-])[O-]
Reactant: C=CC(CO)Oc1ccccc1
Agent: [K+]
Solvent: CO
Product: C=CC(CO)OC(C)(C)C
Reaction time: 8 h

Procedure:
This half-ester R-3k (104 mg; 0.4 mmol) was dissolved in methanol (5 mL) and treated with potassium carbonate (110 mg; 0.8 mmol; 2 equiv.) and stirred overnight to completely consume 3k (tlc analysis). The reaction mixture was diluted with water (25 mL) and ether (25 mL) and the layers were separated. The aqueous layer was extracted with ether (2×15 mL). The combined organic solution was dried (MgSO4) and concentrated to afford 62 mg (94%) of R-1k. All achiral properties of 1k are as reported above. [α]D20 -14.2° (C. 1.01, CH3OH). The absolute configuration of 1k was inferred to be R-(-) by analogy with the absolute configuration results of the enzymatic reaction of 1j. 1H nmr analysis of the MTPA ester using an analogous procedure to that of Dale et al., J. Org. Chem., 1969, 34, 2543, indicated 54% ee for R-1k.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].[F-].[Cs+]>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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([CH3:26])[CH:28]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(Cc3ccccc3)c2=O)cc1C
Temperature: 25 °C
Yield: 56 %

Procedure:
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.4 mmol) prepared in Example 78 was dissolved in anhydrous DME (10 mL) and heated to reflux with 3,4-dimethylbenzeneboronic acid in presence of CsF (146 mg, 0.96 mmol) and tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) for 6 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, providing the desired compound (yield: 100 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 2.15, 2.20 (2s, 3H), 2.25, 2.30 (2s, 3H), 3.05, 3.08 (2s, 3H), 5.35, 5.40 (2s, 2H), 6.60-7.1 (m, 3H), 7.30-7.40 (m, 4H), 7.42-7.60 (m, 2H), 7.70-8.02 (m, 4H). MS (DCI/NH3) m/z 445 (M+H)+. Anal. calc. for C26H24N2O3S.H2O: C, 67.51; H, 5.66; N, 6.05. Found: C, 67.45; H, 5.56; N, 5.85.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:12]4[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Product: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 92 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 4-chloro-3-trifluoromethylphenyl isocyanate, the title compound (48 mg, 92%) was obtained as a pale white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](O)=[O:15])[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:32][NH2:33])=[N:28][C:29]=1[O:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:32][NH:33][C:14]([C:12]2[C:11]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:10][N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=2)=[O:15])=[N:28][C:29]=1[O:30][CH3:31]
Reactant: Cc1cncc(-c2cc(C(=O)O)c(N3CCCC3)cn2)c1
Reactant: COc1ccc(CN)nc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)ncc2N2CCCC2)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-methyl-5-(1-pyrrolidinyl)-2,3′-bipyridine-4-carboxylic acid (2-2, 0.026 g, 0.085 mmol) and 1-(5,6-dimethoxy-2-pyridinyl)methanamine (3-6, 0.017 g, 0.102 mmol) in DMF (0.17 mL) was added HATU (0.032 g, 0.085 mmol) followed by DEA (0.074 mL, 0.426 mmol) and stirred at ambient temperature for 1 h. The system was partitioned between saturated aqueous sodium bicarbonate and EtOAc, washed with brine and dried over magnesium sulfate. Filtration and concentration followed by purification via normal phase chromatography (0→10% MeOH in EtOAc) afforded the title compound (2-3) as a salmon powder. 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 8.40 (m, 1H), 8.32 (s, 1H), 8.06 (m, 1H), 7.08 (s, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 4.63 (d, 2H, J=4.5 Hz), 4.00 (s, 3H), 3.89 (s, 3H), 3.36 (m, 4H), 2.40 (s, 3H), 1.93 (m, 4H). HRMS[M+H]C24H22N5O3 calc'd 434.2187. found 434.2211.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].O.[CH:13]([Cl:16])(Cl)Cl>CN(C)C=O>[Cl:16][C:13]1[CH:5]=[CH:6][C:1]([C:7]2[CH2:8][O:9][C:8](=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:2][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: O=C([O-])Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCC(c2ccc(Cl)cc2)=C1c1ccccc1
Reaction time: 4 h

Procedure:
2-bromine-1-(4-chlorophenyl)-ethanone (2, 102.6 g, 0.44 mol) and potassium phenylacetate (1, 104.5 g, 0.6 mol) are heated to 80° C. in dimethyl formamide (600 mL) while being stirred for 4 hours and are then cooled. After the addition of water (1 L), chloroform is used for extraction (3 times 300 mL), and the chloroform extract is washed with water and then dried (Na2SO4) and concentrated to dryness. For crystallization, diisopropyl ether is added (500 mL) and the crystals, which are formed in the cold [and have] a melting point of 111-113° C., are collected (yield 92 g, 78% with reference to 2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:15][CH2:16][CH:17]=O)[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]([O:15][CH2:16][CH:17]=[N:25][OH:26])[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC=CC[C@H](COCc1ccccc1)OCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC=CC[C@H](COCc1ccccc1)OCC=NO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of {[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}acetaldehyde (C14) (207 g, ≦0.63 mol) and sodium acetate (342 g, 4.17 mol) in aqueous ethanol (2:1 ethanol/water, 2.1 L) was added hydroxylamine hydrochloride (207 g, 2.98 mol). The reaction mixture was stirred at 60° C. for 18 hours, then concentrated in vacuo and extracted with ethyl acetate (2.0 L). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (Eluent: ethyl acetate in petroleum ether) to afford the product as a brown oil. By 1H NMR, this was assigned as a mixture of geometric isomers at both the oxime and olefin functional groups. Yield: 117 g, 0.444 mol, 70% over three steps. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ [7.42-7.48 (m) and 6.88-6.92 (m), total 1H], 7.20-7.36 (m, 5H), 5.29-5.61 (m, 2H), [4.48-4.54 (m) and 4.41-4.45 (m), total 3H], 2.13-2.32 (m, 2H), 1.54-1.65 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].O>CN1C(=O)CCC1>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:4]([C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[CH3:5]
Reactant: CNc1ccc(F)cc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CN(C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of the 2,4-Difluoro-N-methylaniline (Avacado Research Chemical, Heysham UK) (1.43 g, 10 mmole) in NMP, and K2CO3, was added methyl bromoacetate (0.945 ml, 10 mmole) and stirred at room temperature for 24 hours. The reaction mixture was added to water and extracted with ethyl acetate (3×50 ml), the organic extracts were washed 6× with water, dried (MgSO4) and evaporated to give the product as a oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]1)[O:5][CH:6]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].O.O1CCCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]1)[O:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a vial containing ethyl 4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (135 mg, 0.29 mmol) was added water (0.59 mL), tetrahydrofuran (0.591 mL), and methanol (0.59 mL). Lithium hydroxide monohydrate (615.0 mg, 14.6 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The residue was acidified to pH=3 with citric acid (5%). The mixture was extracted three times with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated to give (+/−)-4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (120 mg, 95%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.07 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J=8.0, 4.9 Hz, 1H), 2.04-1.92 (m, 1H), 1.89 (s, 6H), 1.87-1.75 (m, 1H), 1.61-1.36 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). MS (M+1): 433.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](=[O:52])([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:42][CH2:43]Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.CCOC(C)=O>[C:41](=[O:52])([O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[O:42][CH2:43][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: O=C(OCCl)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)Oc3ccccc3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol), TBAB (132 mg, 0.4 mmol) and Et3N (114 μL, 0.8 mmol) in DMF (1 mL) was added chloromethyl phenyl carbonate (46 mg, 0.25 mmol). The reaction was stirred at rt for 12 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to afford the title compound as a white solid (10 mg, 7.7%). The title compound was characterized by LCMS and 1H NMR as shown below: