Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>O1CCCC1>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[O:27])[CH:12]([F:11])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH3:26]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(CF)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(F)C(=O)c1ccccc1
Reaction time: 0.75 h

Procedure:
1.0 M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (13 mL) was added dropwise to α-fluoroacetophenone (1.64 g) in tetrahydrofuran (35 mL) at α-78° C., followed by stirring for 45 minutes. Diethyl oxalate (1.77 mL) was added to the reaction mixture, followed by stirring for 30 minutes. The mixture was further stirred at 0° C. for 1 hour. The resultant mixture was neutralized with 1M aqueous solution of hydrochloric acid. The reaction mixture was partitioned between water and chloroform. Subsequently, the aqueous layer was extracted with chloroform. The organic layers were combined, and washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was evaporated under reduced pressure, to thereby give 3-fluoro-4-phenyl-2,4-dioxobutanoic acid ethyl ester as an oily substance (0.753 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:29])=[C:13]([CH2:20][NH:21]C(=O)OC(C)(C)C)[CH:14]=[CH:15][C:16]=2[CH:17]([F:19])[F:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][CH2:20][C:13]1[C:12]([F:29])=[C:11]([O:10][C:4]2[CH:5]=[C:6]([CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:8]#[N:9])[C:16]([CH:17]([F:19])[F:18])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(F)F)c(Oc2cc(Cl)cc(C#N)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CN)c2F)c1

Procedure:
A solution of 1,1-dimethylethyl {[3-[(3-chloro-5-cyanophenyl)oxy]-4-(difluoromethyl)-2-fluorophenyl]methyl}carbamate (0.152 g, 0.356 mmol) and TFA (1.372 ml, 17.81 mmol) in dichloromethane (10 ml) was stirred for 16 h at RT under an atmosphere of nitrogen. The solution was concentrated under vacuum to give the title compound as an orange oil that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.52 (m, 2H), 7.31 (s, 1H), 7.23-7.26 (m, 1H), 6.89 (s, 1H), 6.74 (t, 1H), 4.19 (br. s., 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl-].[In+3].[Cl-].[Cl-].O[C:13]([CH:25]1[CH2:27][CH:26]1[C:28]#[N:29])([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:14].[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2>ClCCl>[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[C:38]2[C:13]([CH:25]1[CH2:27][CH:26]1[C:28]#[N:29])([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=1)[CH3:14]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3)C3CC3C#N)c[nH]c12

Procedure:
0.02 ml (0.24 mmol) of trifluoroacetic acid and 43.3 mg (0.20 mmol) of indium(III) chloride were added to 50.0 mg (0.20 mmol) of the compound from Example 132A and 69.5 mg (0.39 mmol) of the compound from Example 8A in 2 ml of dichloromethane at RT, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 9.0 mg (11% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)([CH2:27][CH2:28][CH3:29])[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCCC1(c2cccc(OC)c2)CCCC(Br)C1=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: CCCC1(c2cccc(OC)c2)CCCc2sc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21
Temperature: 25 °C
Yield: 2.7 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (100 mg, 0.38 mmol) and of crude 6-bromo-2-(3-methoxy-phenyl)-2-propyl-cyclohexanone (126 mg, 0.39 mmol) in ethanol (5 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (5 mg, 3%) as a yellow solid. MS ISP (m/e): 489.3 (100) [(M+H)−]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.58 (d, 1H), 7.12-7.19 (m, 2H), 6.68-6.89 (m, 5H), 3.76 (s, 6H), 2.67 (m, 2H), 2.29 (s, 3H), 1.05-2.16 (m, 8H), 0.89 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[C:3]1=[O:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.Cl>O1CCCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:3]2([OH:11])[C:2]([CH3:12])([CH3:1])[CH2:7][CH2:6][N:5]3[CH:8]=[N:9][CH:10]=[C:4]23)=[CH:17][CH:16]=1
Reactant: CC1(C)CCn2cncc2C1=O
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(O)c3cncn3CCC2(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.90 mmol of 7,7-dimethyl-6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one in 50 ml of tetrahydrofuran is admixed at 0-5° C. with 15.8 mmol of 4-methoxyphenylmagnesium bromide (0.5M solution in tetrahydrofuran). The reaction solution is subsequently stirred at 0° C. for 1 hour and then at room temperature for 16 hours. The reaction solution is hydrolysed with 0.5N HCl and extracted with tert-butyl methyl ether. The aqueous phase is rendered basic with saturated aqueous sodium hydrogen carbonate solution and the precipitated solid is isolated by filtration and dried. The title compound is obtained as a grey solid and used without further purification for the next stage. Rt=5.42 (Gradient I).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:22]([OH:30])=[C:23]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:31](OCC)(=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:22]4[O:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][C:27](=[O:29])[C:23]=4[CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccc(F)cc3)cc2)c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccc(F)cc4)cc3)c2o1
Yield: 65 %

Procedure:
Following the process described in example 1 (point A), starting from 3'-[(E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethen-1-yl]-2'-hydroxy-acetophenone and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 8:2 (65% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)[N:10]=1.[I-].ClC1C=CC=C[N+]=1C.[C:31]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH3:15][C:13]1[CH:14]=[C:9]([CH3:8])[N:10]=[C:11]([O:16][CH:17]([CH3:21])[C:18]([NH:40][S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[O:20])[N:12]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)nc(OC(C)C(=O)O)n1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)nc(OC(C)C(=O)NS(=O)(=O)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (2.84 g, 0.028 mol) was added to 2.00 g (0.0102 mol) of the product of (b) in dry acetonitrile (100 ml) and then, at 50° C., 3.00 g, 0.0118 mol, of 2-chloro-N-methyl pyridinium iodide was also added. The mixture was stirred at 50° C. for 30 minutes and then 3.32 g (0.0212 mol) of benzene sulphonamide and 1.42 g (0.014 mol) of triethylamine were added and the stirring continued at 50° C. for a further 30 minutes. The mixture was allowed to cool to ambient temperature (~20° C.) and left overnight, stirring being maintained for the entire period. The acetonitrile was then removed by evaporation, 50 ml of water added, the mixture acidified to a pH of 2, 50 ml of diethyl ether added and the solution vigorously stirred for 1 hour. The desired product, a beige solid, formed and was filtered off and dried.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1C[C@H](O)C[C@@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@H](O)C[C@@H]3CO)cc12

Procedure:
In the same manner as in Example 1b (e) and using 3-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (total amount) and N,N-diethyl-2,3-dimethylbenzamide (4.1 g), 3-{2-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one (0.47 g) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.I[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O1CCCC1.CCOCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCSc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](CCl)=[CH:29][N:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:30]3[CH:29]=[N:28][C:27]([Cl:26])=[CH:32][CH:31]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nc3)c2CC1
Yield: 96.3 %

Procedure:
Use a method similar to General Procedure 7, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2 g, 5.2 mmol) and 2-chloro-5-(chloromethyl)pyridine (843 mg, 5.2 mmol) to give 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.2 g, 95%). MS (ES+) m/z: 439.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9](O)[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[F:28][CH:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]2[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1O
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1F
Temperature: 0 °C
Yield: 74 %

Procedure:
A stirred suspension of 4.2 g (0.012 mole) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one in 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm to -10°, and held at this temperature until most of the solid had dissolved. The reaction mixture was poured into ice-water and stirred vigorously. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-hexane to give 3.12 g of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one as light yellow crystals: mp 195°-197° (dec.); 19F nmr (DMSO-d6) δ -113.0 ppm (m, 1F) and -162.1 ppm (d, J=56 Hz, 1F), 1H nmr (DMSO-d6) δ 5.88 ppm (d, J=56 Hz, 1H), 7.2-7.9 ppm (m, 7H), 11.2 ppm (NH).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[S:11][C:12]2[C:18](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O>CS(C)=O>[CH3:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:4][CH:20]3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)sc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nc(C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.1 %

Procedure:
To a suspension of 60% sodium hydride (0.600 g, 15.6 mmol) in dimethyl sulfoxide (10 mL) was added a solution of trimethylsulfoxonium iodide (3.44 g, 15.6 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl-1,3-benzothiazol-7-yl)acrylate (1.60 g, 6.47 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 6 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.62 g, yield 69%).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH3:17].O>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([CH3:17])[CH:12]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccccc1
Yield: 89 %

Procedure:
1.03 mol of a phenylmagnesium chloride solution (26% by weight in THF) are added dropwise in the course of 60 minutes to a boiling solution of 1.0 mol of 2-bromo-5-chlorotoluene and 0.2 g of Pd(dppf) Cl2 *CH2Cl2 in 200 ml of THF. After stirring under reflux for eight hours (conversion >97%), the mixture is hydrolyzed with water. After purification by distillation, 4-chloro-2-methylbiphenyl is obtained as a colorless liquid in a yield of 89%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].O>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:27][CH2:26][C:25]([O:29][CH3:30])=[O:28])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=CC(=O)OC
Solvent: O
Solvent: CCO
Product: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 69.5 %

Procedure:
A mixture of 3.31 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 5 g (0.058 mole) of methyl acrylate in 50 ml of ethanol is heated under reflux for 2 hours. The solution is poured into 10 ml of water and the precipitate is filtered off with suction, washed with methanol and recrystallised from glycol monomethyl ether. 2.9 g (70% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-methoxycarbonylethyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 192° to 194° C. are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[OH:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]4[CH2:27][CH2:28][C@@H:24]([OH:23])[CH2:25]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: O[C@@H]1CCNC1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: O[C@@H]1CCN(CCCCOc2ccc3c(-c4ccc(Cl)cc4)nsc3c2)C1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and (R)-3-Hydroxypyrrolidine were converted to yield (3R)-1-{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol, MS: 403 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:22][C@H:23]1[CH2:25][O:24]1.B(F)(F)F.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:22][C@@H:23]([OH:24])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: C[C@H]1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccccc2)c(C[C@H](C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzyloxy)-2-bromo-4-methylbenzene (3a) (1.0 g, 3.6 mmol) in THF (20 mL) at −78° C. under N2 atmosphere was added n-BuLi (2.5 M, 1.6 mL, 3.9 mmol), the resulting mixture was stirred for 30 min and (S)-2-methyloxirane (0.38 mL, 5.4 mmol) and BF3.Et2O (0.67 mL, 5.4 mmol) were added to the mixture. It was stirred at −78° C. for 1.5 h and warmed up to ambient temperature, quenched with water (10 mL), extracted with EtOAc (30 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (3b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][NH:21][CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CNCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was added methylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of ACOH. The solution was allowed to stir at RT for 1 h followed by the addition of sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resulting mixture was stirred at RT for 16 h and quenched with MeOH. After stirring for 30 min the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel by eluting with EtOAc/MeOH to give 0.62 g (60%) of tert-butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.47 (bs, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s, 3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M+H)+.
Reaction SMILES: [CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22]Br)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22][C:28]2[CH:27]=[C:26]([NH2:25])[CH:31]=[CH:30][N:29]=2)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCc1cc(N)ccn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(2-benzylsulfonylhydrazino)-1-(3-bromopropyl)-6-methylpyrazinone, the product of Example 32, (0.174 g, 0.42 mmol) in dioxane (15 mL), are added 4-aminopyridine (0.048 g, 0.51 mmol) and 2,6-lutidine (0.099 mL, 0.85 mmol). The resulting mixture is stirred at 90° C. for about 15 hours and then is concentrated under reduced pressure. The crude residue is purified by RP-HPLC using acetonitrile/water/trifluoroacetic acid as eluent to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16](N(OC)C)=[O:17])(=[O:3])[CH3:2].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16](=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc2[nH]c(C(=O)N(C)OC)c(NC(C)=O)c2c1
Product: COc1ccc2[nH]c(C(=O)c3ccccc3)c(NC(C)=O)c2c1

Procedure:
The title compound was prepared in an analogous manner to the procedure described in step 3 of Example 125 employing 3-acetylamino-5-methoxy-2-(N-methoxy-N-methylamino)carbonyl indole (step 4) and phenylmagnesium bromide.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4]C.[CH2:20](C1C=NC(C2C=CC(C#N)=CC=2)=NC=1)CCCCC.C(C1C=CC(C2N=CC(C3C=CC(CCCC)=CC=3)=CN=2)=CC=1)#N.C(C1C=CC(C2C=CC(CCCCC)=CC=2)=CC=1)C>>[CH2:1]([C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:20])=[CH:16][CH:17]=2)=[N:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCc1cnc(-c2ccc(C#N)cc2)nc1
Reactant: CCCCCCc1cnc(-c2ccc(C#N)cc2)nc1
Agent: CCCCCc1ccc(-c2ccc(CC)cc2)cc1
Agent: CCCCc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1
Product: CCCCc1cnc(-c2ccc(CC)cc2)nc1

Procedure:
A liquid crystal mixture, in accordance with claim 20, 10.3% p-n-butylbenzoic acid p'-cyanophenyl ester, 11.1% p-n-pentylbenzoic acid p'-cyanophenyl ester, 14.3% p-n-hexylbenzoic acid p'-cyanophenyl ester, 15.4% p-n-heptylbenzoic acid p'-cyanophenyl ester, 11.0% 5-n-pentyl-2-(4-cyanophenyl)pyrimidine, 21.2% 5-n-hexyl-2-(4-cyanophenyl)pyrimidine, 15.6% 2-(4-cyanophenyl)-5-(4-n-butylphenyl)pyrimidine and 15% 4-ethyl-4'-n-pentylbiphenyl.