Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([F:16])[CH:8]=1)([CH3:6])[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:6][C:2]([C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([F:16])[CH:8]=1)([CH3:1])[CH2:3][NH2:5]
Reactant: CC(C)(C(N)=O)c1cc(F)cc2ccoc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN)c1cc(F)cc2ccoc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
A mixture of 0.11 gm (0.49 mMol) 2-methyl-2-(5-fluorobenzofur-7-yl)propionamide and 0.02 gm (0.49 mMol) lithium aluminium hydride in 2 mL tetrahydrofuran was stirred at room temperature for 1 hour. The reaction mixture was then treated sequentially with 38 μL water, 38 μL 15% sodium hydroxide, and 0.11 μL water. The reaction mixture was stirred vigorously for 1 hour and was then filtered. The filtrate was concentrated under reduced pressure to provide 0.018 gm (18%) 2-methyl-2-(5-fluorobenzofur-7-yl)-1-aminopropane. The hydrochloride salt was prepared to provide the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH:6]=[CH:7][NH:8]3)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Oc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ccc23)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaH (1.1 equivalents) is added to a solution of 4-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1.O.[OH-].[K+]>[F:21][C:3]1[C:2]([N:27]2[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1
Reaction time: 13 h
Yield: 63.9 %

Procedure:
A suspension of 3.5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.6 g of 2-methylpiperazine in 40 cm3 of pyridine is heated at a temperature close to 115° C., with stirring, for 13 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at 60° C. The residue is twice taken up with 30 cm3 of ethanol and concentrated under reduced pressure under the above conditions. The solid obtained is taken up in 60 cm3 of water and 10 cm3 of 30% aqueous potassium hydroxide solution. The aqueous phase is washed with twice 100 cm3 of trichloromethane, 10.28 g of methanesulphonic acid are added and the aqueous phase is again washed with twice 100 cm3 of trichloromethane. 10 cm3 of 30% aqueous potassium hydroxide solution are added. The precipitate formed is drained and washed with 3 times 10 cm3 of water and twice 10 cm3 of ethanol. 2.7 g of 7-fluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 360°-363° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([C:11]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=3)=[O:13])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
A mixture of 5.0 g (28.2 mmol) of 6-hydroxy-indole-2-carboxylic acid [J. Chem. Soc. 1605-1608. (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0 g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU (Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at room temperature for 6 h. The precipitated product is filtered off and recrystallized from ethanol to yield 6.75 g (71%) of the title compound. Mp: 214-215° C. (ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:6]#[N:7])[CH3:2].[CH:19]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])([CH3:21])[CH3:20].CC[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:28])=[C:25]([NH2:26])[NH:27][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: CC(C)OC(=O)CC(=N)N
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Yield: 54 %

Procedure:
Upon heating a solution of 12.3 g 2-nitrobenzylidenecyanoacetic acid ethyl ester, 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 ml ethanol for 4 hours, 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester 5-ethyl ester of m.p. 110°C is obtained. Yield: 54% of theory.
Reaction SMILES: Cl.[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([C:13]([F:12])([F:22])[F:23])[CH:15]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)[C@@]1(C)CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@]1(C)CCCN1Cc1cccc(C(F)(F)F)c1
Yield: 47.3 %

Procedure:
The title compound (D10) (47 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride (D3) (60 mg, 0.33 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.076 ml, 0.50 mmol). (Na2CO3: 3 eq; Reaction time: 8 hrs; 60° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][OH:16])/[CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1.ClCCl.[Cl-].[Na+].O>[Si:32]([O:16][CH2:15]/[C:14](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[C:11](/[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)\[CH2:12][OH:13])([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CS(=O)(=O)c1ccc(/C(CO)=C(/CO)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a solution of 110 g of (2Z)-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-ene-1,4-diol and 50 g of imidazole in 1 L of THF stirred at −78° C., a solution 51 g of TBSCl in 250 mL of dichloromethane was added dropwise. The resulting mixture was stirred at −78° C. for 30 min. Brine was then added and warmed to room temperature. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phases were combined and dried over Na2SO4 and evaporated. The resulting crude material was purified by flash chromatography to afford 25.6 g of the title compound as a white solid. 1H NMR (acetone-d6, 500 MHz): a 7.69 (d, 2H), 7.37 (d, 2H), 7.18-7.04 (m, 5M), 4.77 (s, 2H), 4.65 (d, 2H), 3.96 (t, 1H, OH), 3.03 (s, 3H), 0.84 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([NH:22][C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:20][CH:19]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.Cl[C:38]([O:40][CH3:41])=[O:39]>ClCCCl>[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21](=[CH:20][CH:19]=3)[N:22]([C:38]([O:40][CH3:41])=[O:39])[C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])[CH:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)OC2CCCC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 79.5 %

Procedure:
N,N-Diisopropylethylamine (0.148 mL, 0.846 mmol) was added to a solution of (S)-cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.062 g, 0.169 mmol) and methyl chloroformate (0.065 mL, 0.846 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-4-cyclopentyl 1-methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate (0.057 g, 79%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90-1.02 (m, 2 H), 1.02-1.12 (m, 5 H), 1.37-1.93 (m, 9 H), 3.66-3.81 (m, 5 H), 4.49-4.72 (m, 1 H), 5.00-5.21 (m, 1 H), 7.17-7.39 (m, 1 H), 7.67-7.82 (m, 3 H), 8.13 (s, 1 H). MS (ESI, pos. ion) m/z 425. [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19].ClC1C=C(C=CC=1)C(OO)=[O:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:13]([S:10]([C:6]1[CH:5]=[CH:4][C:3]([NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:19])([F:21])[F:20])=[C:2]([Cl:1])[C:7]=1[S:8]([CH3:9])=[O:30])(=[O:12])=[O:11])[CH3:14]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1SC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1S(C)=O
Reaction time: 16 h
Yield: 132.3 %

Procedure:
To a stirred solution of (R)-N-[4-ethylsulphonyl-3-methylsulphanyl-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 28) (0.636 g) in DCM was added metachloroperoxybenzoic acid (0.17 g). After 1 hour at ambient temperature a further portion of meta-chloroperoxybenzoic acid (0.14 g) was added and stirring was continued at ambient temperature for 16 hours. Further meta-chloroperoxybenzoic acid (0.08 g) was added and after 30 minutes sodium hydrogen carbonate solution (50 ml) was added. The organic layer was separated, dried and volatile material was removed by evaporation. The residue was purified by chromatography on a Mega Bond Elut column (20 g) eluting with 10-80% EtOAc/isohexane to give the title compound (0.55 g) as a white foam. NMR: 1.19 (t, 3H), 1.62 (s, 3H), 3.14 (s, 3H), 3.52-3.60 (m, 2H), 8.00 (d, 1H), 8.14 (brs, 1H), 8.45-8.49 (m, 1H), 10.11 (brs, 1H); m/z: 420.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([CH3:41])[CH2:36][CH2:35]2)=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].C(O)(=O)C>C(O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[C:31]([N:34]5[CH2:40][CH2:39][CH2:38][N:37]([CH3:41])[CH2:36][CH2:35]5)[CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCN(C)CC2)ccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.549 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)benzamide (0.270 g) and glacial acetic acid (0.047 ml) in ethanol (5 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in methylene chloride and washed with a saturated NaHCO3 solution. The organic phase was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.102 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.67 (m, 2H), 1.91 (m, 2H), 2.11 (s, 3H), 2.24 (s, 3H), 2.44 (m, 2H), 2.64 (t, 2H), 2.84 (m, 1H), 3.52 (t, 2H), 3.60 (t, 2H), 7.22 (d, 1H), 7.36 (m, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.78 (d, 1H), 7.87 (m, 1H), 7.96 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:21])[CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1>C(O)C.C(COC)OC>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]([OH:21])[CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: O=C1CC(c2ccc3c(c2)OCO3)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O[C@@H]1C[C@H](c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Sodium borohydride (1.5 g) was added in portions with stirring at 10-15° C. to a solution of 3-(benzo[1,3]dioxol-5-yl)-indan-1-one (10 g) in a mixture of ethanol (75 mL) and dimethoxyethane (75 mL). The mixture was stirred at rt for 1 h and then evaporated in vacuo. The resulting oil was treated with water and diethyl ether, and the organic phase was separated and washed with water and 0.1 N HCl, dried (MgSO4) and evaporated in vacuo to give cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol as a brown oil (10 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=O)(=[O:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C(C)=CC=CC=1C>ClCCl>[CH2:21]([NH:28][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Oc1cc(C(=O)O)cc([N+](=O)[O-])c1OC(C)=O
Reactant: NCc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)NCc2ccccc2)cc([N+](=O)[O-])c1OC(C)=O

Procedure:
0.75 g of 3,4-diacetoxy-5-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was dissolved in 5 ml of dichloromethane and added to a solution containing 0.27 ml of benzylamine and 0.5 ml of 2,6-lutidine in 7 ml of dichloromethane. Yield 0.95 g (96%), a viscous oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:53]1([CH2:59][CH2:60][CH2:61][NH:62][C:63]([C:65]2[N:70]=[CH:69][C:68](OS(C(F)(F)F)(=O)=O)=[CH:67][CH:66]=2)=[O:64])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.[N:79]1([C:85]([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][C:88]=2[C:93]([F:96])([F:95])[F:94])=[O:86])[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:53]1([CH2:59][CH2:60][CH2:61][NH:62][C:63]([C:65]2[CH:66]=[CH:67][C:68]([N:82]3[CH2:83][CH2:84][N:79]([C:85](=[O:86])[C:87]4[CH:92]=[CH:91][CH:90]=[CH:89][C:88]=4[C:93]([F:96])([F:94])[F:95])[CH2:80][CH2:81]3)=[CH:69][N:70]=2)=[O:64])[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(NCCCc1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(NCCCc1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 25 °C
Yield: 13 %

Procedure:
A 50-mL flask was charged with cesium carbonate (0.078 g, 0.238 mmol), palladium diacetate (0.0019 g, 0.0085 mmol) and BINAP (0.0079 g, 0.013 mmol) and flushed with argon for 30 minutes. A solution of trifluoromethanesulfonic acid 6-(3-phenylpropylcarbamoyl)pyridin-3-yl ester (0.066 g, 0.17 mmol) and piperazin-1-yl-(2-trifluoromethylphenyl)methanone (0.053 g, 0.20 mmol) in toluene (2 mL) was added via syringe. The reaction mixture was heated at 100 C for 26 h, cooled to room temperature, diluted with toluene (20 mL), filtered and concentrated in vacuo. The crude product was purified by column chromatography to afford the title compound as a white solid (0.011 g, 13% yield). 1H NMR (300 MHz, CDCl3) δ 8.15, 8.04, 7.85, 7.74, 7.50-7.65, 7.36, 7.30-7.10, 3.90-4.10, 3.55-3.30, 3.22, 2.72, 1.96. MS (ES+) m/z 497.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16](Cl)(=O)[CH3:17]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCO
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCCO
Reaction time: 24 h
Yield: 833.6 %

Procedure:
In a 100 mL two-neck flask with a reflux condenser and magnetic anchor, under a static flux of nitrogen, 12-hydroxy-dodecanoic acid (5.0 g, 23.2 mmol) is weighed, ethanol (20 mL) and acetyl chloride (1.62 mmol, 0.09 ml, 0.1 eq.) are added. The mixture is left stirring in reflux conditions for 24 hours. It is concentrated in the Rotavapor and in the high vacuum pump and the product is purified with column chromatography on silica gel with eluant mixture petroleum ether/ethyl acetate 5/4. 3.30 g of ethyl 12-hydroxydodecanoate are isolated as a light yellowish oil for a yield of 96%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(-c4cccc(Cl)c4)c3)cc1)n2C1CCCCC1
Yield: 85.6 %

Procedure:
Ethyl 2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (65 g) obtained in Example 1 and 3-chlorophenylboronic acid (23 g) were treated in the same manner as in Example 5 to give the title compound (59 g, yield 85%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3].[CH:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:16])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method 64, 1 g, 6.54 mmol), cyclopropyl carboxylic acid (0.62 ml, 7.84 mmol), HATu (2.5 g (6.57 mmol), and DIEA (2.3 ml, 13.08 mmol) in DMF (15 ml). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with water and partitioned with EtOAc. The layers were cut, followed by an additional wash of the aqueous with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was then purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 5-15% EtOAc in DCM to give 458 mg of the title compound (32% isolated yield). 1H NMR: 10.16 (s, 1H) 8.53 (dd, J=7.91, 2.26 Hz, 1H) 7.67-7.82 (m, 1H) 7.40 (dd, J=10.55, 8.67 Hz, 1H) 2.54 (s, 3H) 1.95-2.09 (m, 1H) 0.78-0.88 (m, 4H).
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
A mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene (1.3 g) obtained by the above-mentioned reaction, methyl 4-aminobenzoate (1.1 g), sodium carbonate (0.8 g) and sodium iodide (2.2 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give methyl 4-[(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methyl)amino]benzoate as an amorphous compound. The obtained methyl 4-[(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methyl)amino]benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (1.5 mL) was added, and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.7 g, 43%) as an amorphous compound.