Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:19][O+](C)C>C(#N)C>[F:14][B-:15]([F:18])([F:17])[F:16].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N+:5]([CH3:19])=[C:4]([CH3:13])[CH:3]=1
Reactant: C[O+](C)C
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Cc1cc(Cl)c2cc(Cl)ccc2[n+]1C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
The starting material may be prepared as follows. Powdered 4,6-dichloro-2-methylquinoline (254 mg.) was added to a stirred solution of trimethyloxonium tetrafluoroborate (177 mg.) in acetonitrile (1 ml.), and stirring was continued overnight. The solvent was evaporated and the residue was triturated with ether to give 4,6-dichloro-1,2-dimethylquinolinium tetrafluoroborate (296 mg.). N.m.r. in solvent A: 3.07(s, 3H); 4.44(s, 3H); 7.9-8.8(complex, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1.O>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:17][CH:18]=1.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:21])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCc1cccc(Br)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 16 h
Yield: 187.6 %

Procedure:
4-Methylbenzenesulphonyl chloride (4.38 g) was added portionwise to a solution of 3-bromobenzeneethanol [Example H(a)] (2.30 g, 11.4 mmol) in pyridine (30 ml) at 0° C., and the mixture stood at -20° C. for 16 h. The mixture was diluted with water, extracted with diethyl ether, the extracts combined, washed twice with aqueous 4N hydrochloric acid and once with saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to afford a pale yellow oil (3.98 g). [M-OTs]+ 182; 360 MHz 1H n.m.r (CDCl3) 7.66 (2H, d, J 8.3 Hz), 7.34 (1H, dm, J 7.9 Hz), 7.30-7.26 (2H, m), 7.20 (1H, d, J 1.5 Hz), 7.12 (1H, t, J 7.7 Hz), 7.05 (1H, d, J 7.7 Hz), 4.20 (2H, t, J 6.8 Hz), 2.91 (2H, t, J 6.8 Hz), 2.44 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[Li]CCCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCCC1.[Hg]>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([O-:11])(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)C2CC=C(CCO)C1C2
Agent: [Hg]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: -78 °C
Yield: 90 %

Procedure:
A dry, 2-L flask equipped with a septum inlet, magnetic stirring bar, and a reflux condenser leading to a mercury bubbler was flushed with dry nitrogen and maintained under static pressure of nitrogen. The flask was charged with 170 mL (1 mol) of (-)-nopol [[α]23D 40.2 (neat)] and 400 mL tetrahydrofuran (THF) and cooled to -78° C. While the solution was stirring at -78° C., 455 mL (2.2M, 1 mol) of n-BuLi was added slowly and stirred for 1 h at -78° C.; 190 g (1 mol) of p-toluenesulfonyl chloride in 200 mL of THF was added slowly and the stirring continued for another hour at at -78° C. It was then warmed to room temperature and stirred for 2 h. The reaction mixture was poured into ice-water and extracted with pentane. Evaporation of the solvent gave a thick semi-solid of nopol tosylate in 90% yield (290 g). Nopol tosylate (290 g) was dissolved in hot pentane (800 mL) and stored at 0° C. for 12 h to insure complete crystallization. Colorless white needles of Nopol tosylate (mp 50°-51° C.) were recovered by fast filtration in 85% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH:14]([C:16]1[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2)=[O:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:15])[C:16]2[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(O)c2ccc(Br)cn2)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in 50 mL of toluene at −78° C. was added n-butyllithium (2.5 M in toluene, 4.05 mL, 10.1 mmol) dropwise. After 2 h, a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (1.86 g, 7.60 mmoL) in 50 mL of dichloromethane was added dropwise. The mixture was warmed to rt, and after 1 h, treated with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes to provide ethyl 1-[(5-bromopyridin-2-yl)(hydroxyl)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 404.7 (81Br) for [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20]C(O)[CH2:22]2.[Na]>C1(C)C=CC=CC=1>[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20][CH:10]([O:9][C:7]([C:6]([OH:11])([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22]2
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Reaction time: 5 h

Procedure:
50.87 g (0.2 mole) of methyl di-(2-thienyl)glycolate and 31.04 g (0.2 mole) of scopine are dissolved in 100 ml of absolute toluene and reacted at a bath temperature of 90° C. with addition of 1.65 g (0.071 gram atom) of sodium in several portions. The resulting methanol is distilled off at a reaction mixture temperature of 78°-90° C. under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase is separated off, rendered alkaline using sodium carbonate and the free base is extracted using methylene chloride. After drying over sodium sulphate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallised from acetonitrile; beige-coloured crystals (from acetonitrile).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH3:19])[C:12](=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15].CCOC(C)=O.O>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][C:11]=1[CH3:19]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1nc(-c2ccccc2)sc1C

Procedure:
A solution of 13.13 g (95.7 mmol) of thiobenzamide and 5.0 g (23.9 mmol) of methyl 4-bromo-3-oxo-pentanoate in 25 mL of dry toluene was heated at 90° C. for 5 h. The solution was poured into EtOAc/water and the aqueous phase extracted with EtOAc. The organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude oil was purified by silica gel chromatography eluting with hexanes/EtOAc (3/1 to 2/1) to afford 4.14 g (70%) yield) of the title compound as a pale orange-colored oil: 1H NMR (CDCl3, 400 MHz) δ7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Brc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 10.7 g of 3-bromo-1H-pyrazole, 11.8 g of 2,3-dichloropyridine, 57.3 g of cesium carbonate and 80 mL of N,N-dimethylformamide was stirred at 100° C. for 8 hours. After cooling to room temperature and adding water, the reaction mixture was extracted twice with methyl tert-butyl ether. The organic layers were combined, washed sequentially with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 12.9 g of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine. 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].COC(=O)[O-].[CH3:18][NH+:19]1[CH2:23][CH:22]([CH3:24])[N:21]([CH3:25])[CH:20]1[CH3:26]>>[CH3:18][NH+:19]1[CH2:23][CH:22]([CH3:24])[N:21]([CH3:25])[CH:20]1[CH3:26].[C:1]([O-:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-:6])=[O:5]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Product: O=C([O-])c1ccccc1C(=O)[O-]

Procedure:
Next, phthalic acid (0.1 mol) was added into a 1,2,3,4-tetramethyl imidazolinium methyl carbonate salt (0.1 mol) solution to induce a salt exchange reaction, thereby obtaining a 1,2,3,4-tetramethyl imidazolinium•phthalate solution.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH:20]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cccc(-c2ccc(Cl)cc2)c1
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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(-c3ccc(Cl)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.9 grams (0.012 mole) of 3-(4-chlorophenyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-(4-chlorophenyl)phenyl]pyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](O)[CH3:25]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:24][CH3:25])=[O:9])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccncc1

Procedure:
A solution of 4-pyridylacetic acid in 500 ml of anhydrous ethanol containing 75 ml of concentrated sulfuric acid is refluxed 18 hours. The solution is cooled to 0° an neutralized by addition of sodium hydroxide solution and saturated aqueous sodium carbonate. Extraction with ethyl acetate yields on concentration in vacuo ethyl 4-pyridylacetate.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:21][C:22]1[N:23]=[CH:24][N:25]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
A suspension of triphenylmethyl chloride in anhydrous DMF (100 ml) was slowly added to a stirred solution of 4-methylimidazole (12.30 g) and triethylamine (41.8 ml) in anhydrous DMF (200 ml). After stirring the resultant slurry for ca. 3 h it was added to water (750 ml) and the solid removed by filtration. The solid was dissolved in dichloromethane (500 ml) and residual water separated. The organic solution was dried and evaporated to dryness to give the title compound as a white solid (42.7 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19](C3CCCCO3)[CH:18]=[N:17][N:16]=2)[CH:12]=[CH:11][C:10]=1[C:26]1[N:31]=[C:30]2[NH:32][C:33]3([CH2:38][CH2:37]3)[C:34](=[O:36])[NH:35][C:29]2=[N:28][CH:27]=1.CC1C=C(C2N(C3CCCCO3)C=NN=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1N=C2NC3(CC3)C(=O)NC2=NC=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)(C)C.O1CCOCC1>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:19][CH:18]=[N:17][N:16]=2)[CH:12]=[CH:11][C:10]=1[C:26]1[N:31]=[C:30]2[NH:32][C:33]3([CH2:37][CH2:38]3)[C:34](=[O:36])[NH:35][C:29]2=[N:28][CH:27]=1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1cc(-c2nncn2C2CCCCO2)ccc1B1OC(C)(C)C(C)(C)O1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Temperature: 100 °C
Yield: 38 %

Procedure:
7′-(2-Methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one trifluoroacetate. 3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (See Example 2.C) (0.201 g, 0.545 mmol), 7′-bromo-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one (0.139 g, 0.545 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.045 g, 0.054 mmol), sodium carbonate (1 M in water, 1.635 mL, 1.635 mmol), 1,4-dioxane (1.2 mL) and isopropanol (0.4 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 100° C. for 1 h. The resulting mixture was diluted with water and extracted three times with dichloromethane. The combined organics were concentrated under reduced pressure. The residue was taken up in DMSO and methanol, filtered and purified using reverse-phase preparatory HPLC (20-70% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under high vacuum to give the desired product (0.109 g, 0.205 mmol, 38% yield) as an orange solid. MS (ESI) m/z 418.4 [M+1]+.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6](O)[CH2:7][CH2:8][OH:9]>P(=O)(O)(O)O>[CH2:2]([CH:1]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: OCCCO
Agent: O=P(O)(O)O
Product: CCCC1OCCCO1
Yield: 56 %

Procedure:
This example illustrates the limitations of conventional synthesis methods. A 500 mL round bottom was charged with 191 g normal butyraldehyde, 101 g of 1,3-propanediol, and 4 drops 85% phosphoric acid. The round bottom was fitted with a Dean-Stark trap and condenser and the entire apparatus was placed into an electric heating mantle and brought to reflux. The aldehyde/water azeotrope condensed and separated into the trap. Heating was maintained until 24 mL of water had evolved (1 hr). The mixture was cooled and poured into a separatory funnel. The solution was washed twice with 50 mL of saturated sodium bicarbonate solution and once with 50 mL of distilled water. The organics were dried over MgSO4 and the residue distilled. A fraction collected at 150° C. was 99.6% acetal and had a mass of 95.7 g. This corresponds to a yield of 56%, lower than the yields reported in Table II.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 10.00 g of p-toluoyl chloride in 300 ml of dichloromethane, 6.94 g of N,O-dimethylhydroxyamine hydrochloride was added. The reaction solution was ice-cooled and 11.5 ml of pyridine was added dropwise. After the completion of dropwise addition, the mixture was stirred at room temperature for one hour and the solvent was evaporated under reduced pressure. The residue was combined with water, extracted with diethyl ether and then washed in turn with 10% hydrochloric acid, water and an aqueous saturated sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 10.40 g of the desired compound as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][C@H:59]([CH3:81])[CH2:60][O:61][C:62]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:55]=[C:54]([S:82][CH2:83][C:84]2[CH:89]=[CH:88][CH:87]=[C:86]([F:90])[C:85]=2[F:91])[N:53]=1>O1CCOCC1.C(Cl)Cl.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]>[F:91][C:85]1[C:86]([F:90])=[CH:87][CH:88]=[CH:89][C:84]=1[CH2:83][S:82][C:54]1[N:53]=[C:52]([NH:10][S:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:57]=[C:56]([O:58][C@H:59]([CH3:81])[CH2:60][O:61][C:62]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[N:55]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)c1ccncc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of 4-pyridinesulfonamide (the product from step i) (0.21 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.66 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product from step iii) (0.40 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 3 h. The reaction mixture was diluted with DCM, filtered through arbocel and the filtrate evaporated. The residue was purified by reverse phase HPLC using a TFA (0.2%)/MeCN system to give the title compound as a yellow solid. Yield: 0.21 g.
Reaction SMILES: [K].Br[CH:3]([CH:7]([CH3:9])[CH3:8])[C:4]([OH:6])=[O:5].[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH:13][C@H:3]([C:4]([OH:6])=[O:5])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Cl)cc1F
Agent: [K]
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
N-(2-fluoro-4-chlorophenyl)valine and m-phenoxybenzyl bromide are reacted using the process of Example 42 to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 427.1 (M+, 4.1), 200 (100). N-(2-fluoro-4-chlorophenyl)-valine is prepared by heating the potassium salt of α-bromoisovaleric acid and 2-fluoro-4-chloroaniline neat at 130° for about 2 hours.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5](=[O:25])[CH2:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH:9]=1)C.[OH-].[Na+]>CO.O>[O:25]=[C:5]([CH2:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH:9]=1)[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1
Reaction time: 4 h

Procedure:
Isomer A: 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid ethyl ester (isomer A from above) was dissolved in 2 mLs methanol, and to it was added 1 mL of a 1M solution of sodium hydroxide in water. After stirring for 4 hr, the reaction was poured into 5 mL sodium hydroxide and extracted three times with diethyl ether. The aqueous layer was then acidified via the addition of excess 10% citric acid and extracted three times with ethyl acetate. The ethyl acetate extracts were combined and washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The residue was triturated in 3:1 hexane/diethyl ether, filtered and the solvent removed in vacuo to yield the title compound as a yellow solid. 1H NMR (CDCl3) δ1.72-1.91(3H,m), 2.20(1H,m), 2.80-3.00(2H,m), 4.22(1H, t, J=7.14Hz), 6.77(1H, d, J=7.69 Hz), 7.03(1H, t, J=7.42Hz), 7.11-7.19(3H,m), 7.31(1H, d, J=7.69Hz), 7.41(1H, t, J=7.69Hz), 7.80(1H,s), 7.84(1H, d, J=7.88Hz).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](Cl)(=[O:11])[CH3:10].Cl>N1C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]([O:7][C:9]([CH3:10])=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)cc1
Yield: 92.9 %

Procedure:
A mixture of 65.0 g (0.60 mol) of p-cresol, 51.8 g (0.66 mol) of acetyl chloride, and 6 mL of anhydrous pyridine was refluxed for 1.5 h and then added to 600 mL of 2% hydrochloric acid. The product was extracted with 2×100 mL of diethyl ether, the combined extract was washed with 2% NaOH, then dried over Na2SO4, and evaporated to dryness. Drying the residue in vacuum gave 83.7 g (93%) of p-tolyl acetate (bp 104-105° C./25 mm Hg). A mixture of 40.0 g (0.27 mol) of p-tolyl acetate and 45.0 (0.34 mol) of AlCl3 was slowly heated to 120-125° C. for 30 min. The mixture was stirred for 1 hr and then 500 mL of 2M HCl was added at 0° C. The product was extracted with 3×100 mL of diethyl ether, the combined extract was dried over Na2SO4 and then evaporated to dryness. This gave 39.7 g (99%) of the title product which was further used without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[N:18]1([C:24]2[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH2:16][N:21]2[CH2:20][CH2:19][N:18]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1

Procedure:
reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, ethyl 4-piperazin-1-ylbenzoate and a first reducing agent and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate;