Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:18]1[C:24]2[CH2:23][NH:22][C:25]3[CH:26]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:4]=2[CH:3]=[CH:2][CH:19]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 5,11-dihydro-10-dibenz [b,e][1,4]diazepine 1.9 g of 4-[(2-methylbenzoyl) amino]benzoyl chloride, 4 ml of triethylamine and 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is poured into ice water and the separated organic layer washed with 50 ml each of water, 2N HC1, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and the solvent removed to give a residue. The residue is chromatographed on a silica gel column using 1:4 ethyl acetatehexane to give 1.8 g of the desired product as a solid, m.p. 68°-71° C.
Reaction SMILES: [N+:1]([C:4]1[C:9](F)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].Cl.[C:12]([N:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>CS(C)=O>[N+:1]([C:4]1[C:9]([N:25]2[CH2:26][CH2:27][N:22]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:23][CH:24]2[C:28]([OH:30])=[O:29])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1cccnc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A mixture of 2.8 g. of 2-nitro-3-fluoropyridine, 5.0 g. of 4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 25 ml. of triethylamine, and 90 ml. of dimethyl sulfoxide is heated at 55° with stirring for 11/2 hours, then allowed to stand at room temperature overnight. A similar workup to that described in Example 1 gives 4.5 g. of the title product as a viscous orange glass. Thin layer chromatographic analysis of this material shows one single spot.
Reaction SMILES: Cl.[C:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[C:5]([O:4][C:2](=[O:3])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of N-Boc 1, 6-diaminohexane hydrochloride (1.51 g, 6 mmol) and triethyl amine (1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride (2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil (2.1 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.P(Cl)(Cl)([Cl:18])=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([Cl:18])=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)Cn1cc(Br)c(O)c(C#N)c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Cn1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4-hydroxy-1-isobutyl-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B (6.6 g) and phosphorus oxychloride (0.126 mL) was heated at 120° C. for 24 hr, and cooled to room temperature. The reaction mixture was poured into water, and the pH was adjusted to 10 with potassium carbonate. The reaction mixture was extracted with ethyl acetate. The extract was washed with washed with water and 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 (petroleum ether/ethyl acetate) to give the title compound (4.60 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:3]1=[O:31].[Li+].CC([N-]C(C)C)C.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][N:43]=1>C1COCC1.CC(=O)OCC.O>[OH:47][CH:46]([C:45]1[CH:44]=[N:43][C:42]([C:41]([F:51])([F:40])[F:50])=[CH:49][CH:48]=1)[C:11]1[C:6]2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:3](=[O:31])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cncc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cncc(Oc2cnc3c(c2C(O)c2ccc(C(F)(F)F)nc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
To a solution of 1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 27, step 1, 140 mg, 0.330 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 0.84 mL, 1.65 mmol) dropwise The reaction was stirred at −78° C. for 1 h then a solution of 6-(trifluoromethyl) nicotinaldehyde (115 mg, 0.660 mmol) in THF (2 mL) was added. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (24 mg, 12.1% yield) as a yellow oil. LCMS: [MH+-THP] 518 and TR=1.494 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:26])[CH3:25])[C:19]([C:27]([N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[O:28])=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:36]=[S:32]1(=[O:35])[CH2:33][CH2:34][N:29]([C:27]([C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=3)=[O:28])[CH2:30][CH2:31]1
Reactant: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a cold (0° C.) mixture of 4-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-1-isopropyl-1H-indol-5-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (410 mg, 1.0 eq.) in dichloromethane (8 mL) was added dropwise trifluoroacetic acid (920 mg, 10 eq.). The mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was partitioned between a potassium carbonate aqueous solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and dried in vacuo. The residue was then purified on silica eluting with dichloromethane/methanol/ammoniac 95:5:0.25 v:v:v. to yield 296 mg (86%) of the desired product as off-white oil. MS (m/e): 420.4 (MH+, 100%).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:1][NH:2][CH2:3][C@H:4]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7]
Reactant: C=CC[C@H](C(=O)NC)c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CC[C@H](CNC)c1ccc(F)cc1
Reaction time: 2.5 h

Procedure:
Combine (S)-2-(4-fluorophenyl)pent-4-enoic acid, N-methyl amide (3.1 g, 14.96 mmol) and tetrahydrofuran (35 mL). Cool in an ice bath, add a solution of lithium aluminum hydride (35 mL, 1.0 M in tetrahydrofuran, 35 mmol). After the addition is complete, heat the reaction mixture to reflux. After 2.5 hours, cool in an ice bath and carefully quench with water (1.3 mL), an aqueous 15% sodium hydroxide solution (1.3 mL), and then water (4 mL). Dilute the quenched reaction mixture with diethyl ether (75 mL) , add MgSO4, and stir. After 1 hour, filter through celite and rinse the solids with dichloromethane. Evaporate the filtrate in vacuo to give (S)-N-methyl-(2-(4-fluorophenyl)pent-4-enyl)amine: Rf=0.47 (silica gel, 18.5/1.5/0.2 dichloromethane/methanol/concentrated aqueous ammonia).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[O:17]1CCC[CH2:18]1.C(Cl)(Cl)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:18]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(NNc1ccc(F)cc1)c1cccs1
Reactant: C1CCOC1
Agent: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1oc(-c2cccs2)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
N′-(4-fluorophenyl)thiophene-2-carbohydrazide (575 mg, 2.43 mmol) was dissolved in dichloromethane (14 mL) and tetrahydrofuran (10 mL) in a glass flask. The flask was cooled in ice. Phosgene (20% in toluene, 3.42 mL, 6.49 mmol, 2.67 eq.) was added, and the solution was stirred overnight under a nitrogen atmosphere, allowing it to warm to room temperature. Ethyl acetate (40 mL) was added, and the solution was then washed with water (2×25 mL) and brine (25 mL). The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.59 grams of crude product as a light brown solid. Purification using ISCO flash chromatography (silica, gradient heptanes/ethyl acetate) gave 3-(4-fluorophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazol-2(3H)-one (210 mg, 0.800 mmol, yield 33.0%) as an off-white solid with an HPLC purity of 99.7%. LC-MS [M+H] 263.02 (C12H7FN2O2S+H, expected 263.02). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][O:38][CH3:39]>CS(C)=O>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:36][CH2:37][O:38][CH3:39])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Reaction time: 6 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide ((for a preparation see Example 36)101 mg, 0.254 mmol) in DMSO (1 ml) was added cesium carbonate (166 mg, 0.508 mmol) and then 1-bromo-2-(methyloxy)ethane (0.035 ml, 0.372 mmol, Aldrich) under nitrogen at ambient temperature. The solution was stirred for 6 h. The mixture was filtered using a hydrophobic frit and the filtrate diluted with methanol (1 ml). The filtrate was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a pale yellow gum (35 mg); LCMS: (System 4) MH+=456, tRET=2.84 min.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C(P(C)C)P(C)C.CC(C)([O-])C.[Na+].N#N.Cl[C:29]1[N:34]=[C:33]([NH:35][C@H:36]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH3:37])[CH:32]=[CH:31][CH:30]=1.[NH2:45][C:46]1[CH:50]=[C:49]([CH:51]2[CH2:53][CH2:52]2)[N:48]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[N:47]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:51]1([C:49]2[N:48]([C:54]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:55])[N:47]=[C:46]([NH:45][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([NH:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[CH3:37])[N:34]=3)[CH:50]=2)[CH2:52][CH2:53]1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Reactant: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CP(C)C(c1ccccc1-c1ccccc1)P(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cccc(Nc2cc(C3CC3)n(C(=O)OC(C)(C)C)n2)n1)c1ccc(F)cc1
Temperature: 110 °C
Yield: 36.3 %

Procedure:
To a 25 ml round bottom flask was added Pd2(dba)3 (84 mg, 0.092 mmol), (biphenyl-2-ylmethylene)bis(dimethylphosphine) (55 mg, 0.184 mmol) and sodium tert-butoxide (132 mg, 1.38 mmol). The flask was sealed and refilled with N2. To the mixture was added a solution of 6-chloro-N-[(1S)-1-(4-fluorophenyl)ethyl]pyridin-2-amine (Method 20; 230 mg, 0.92 mmol) and tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (223 mg, 1.0 mmol) in toluene (4 ml). The reaction mixture was heated at 110° C. overnight. Solvent was removed and EtOAc was added and the mixture was washed with brine and was concentrated. Flash chromatography (15-40% EtOAc in hexanes) gave the title compound (146 mg, 36%). 1H NMR (CDCl3) δ 0.80-1.00 (m, 4H), 1.60 (m, 3H), 1.65 (s, 9H), 1.95 (m, 1H), 4.71 (m, 1H), 4.75 (m, 1H), 5.75 (m, 1H), 6.09 (m, 1H), 6.21 (s, 1H), 7.00 (m, 2H), 7.23 (m, 2H), 7.30 (m, 1H), 9.40 (s, 1H).
Reaction SMILES: Br[SiH3].[F:3][C:4]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:6][Si:7](Br)([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[C:23]([Mg]Br)#[CH:24]>C1COCC1>[F:3][C:4]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:6][Si:7]([C:23]#[CH:24])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9]
Reactant: C#C[Mg]Br
Reactant: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)F)C(C)C
Agent: [SiH3]Br
Solvent: C1CCOC1
Product: C#C[Si](CCC(F)(F)C(F)(F)C(F)(F)F)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 90 %

Procedure:
In an oven dried round bottom flask, (3,3,4,4,5,5,5-heptafluoropentyl)diisopropylsilane (10 g, 32 mmol) was dissolved in allyl bromide (20 mL) and the flask was flushed with N2. PdCl2 (40 mg) was added and the solution was heated to 60° C. for 12 hr. Solvent was removed on a rotary evaporator to yield a brown suspension that was taken up in pentane and filtered. Solvent removal yielded the bromosilane as a brown liquid (12.1 g). The bromosilane, (3,3,4,4,5,5,5-heptafluoropentyldiisopropylsilyl)bromide, was treated with ethynylmagnesium bromide (70 mL, 35 mmol, 0.5 M in THF) in anhydrous THF (20 mL) and heated to 40° C. for 4 hr. After cooling, the reaction was quenched by the slow addition of water (20 mL) and dilute sulfuric acid sufficient to dissolve the magnesium salts. Pentane was added and the organic layer was separated. The aqueous layer was extracted with pentane an additional time, then the organic layers were combined, washed with water (5×10 mL) and brine, dried over MgSO4, and filtered. Solvent was removed and the crude product was taken up in hexane and rinsed through a thin pad of silica. Solvent removal yielded the product as a colorless liquid (9.7 g, 29 mmol, 90%). Analysis of the product provided the following data: 1H-NMR (400 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.0 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(ccn2Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (49 mg, 0.13 mmol) in DMF (1 mL) and add sodium hydride (17 mg, 0.42 mmol). Stir the mixture at room temperature for 30 min then add 2-bromomethyl-pyridine hydrobromide (35 mg, 0.14 mmol). Stir the mixture at room temperature for 5 h, then dilute with EtOAc (30 mL) and wash with saturated NaHCO3 (10 mL). Dry, filter and concentrate the organic solution. Purify the crude material by flash chromatography, using a linear gradient of 20% to 80% EtOAc/hexanes as eluent, to give the title compound (32 mg, 52%). MS (ES+) 471.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 8.55-8.53 (m, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.73 (dt, 1H, J=7.7, 1.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.57-7.55 (m, 2H), 7.45 (d, 1H, J=8.8 Hz), 7.30-7.26 (m, 1H), 7.10 (dd, 1H, J=8.6, 2.0 Hz), 7.03 (d, 1H, J=7.9 Hz), 6.52 (d, 1H, J=3.5 Hz), 5.53 (s, 2H), 4.10 (t, 2H, J=7.0 Hz), 3.27 (t, 2H, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[NH:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH3:16][C:17](C)([O-])C.[K+].C(I)C>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:16]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH:13]=[O:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15])[CH3:17]
Reactant: COc1cc2c(cc1C=O)NC(=O)CC2
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1C(=O)CCc2cc(OC)c(C=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde (preparation 3) 60 mg (0.293 mmol) was dissolved in 5 ml of anhydrous THF and the solution was cooled to 0° C. The reaction mixture was treated with 33 mg (0.293 mmol) of potassium t-butoxide whereupon it became yellow in color. After stirring for 30 minutes, the mixture was treated with 23 μl (0.293 mmol) ethyl iodide and slowly warmed to room temperature while stirring for 16 hours (h). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to an oil. The residue was chromatographed on silica gel eluting with 6/4 ethyl acetate/hexane to afford 34 mg (40%) as a white solid. MS APCI m/e 234 (p+1)
Reaction SMILES: Br[C:2](=[CH:4][CH3:5])[CH3:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[CH:3]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7])=[CH:2][CH2:4][CH3:5]
Reactant: CC=C(C)Br
Reactant: O=[N+]([O-])c1ccccc1O
Product: CCC=COc1ccccc1[N+](=O)[O-]

Procedure:
2-Bromo-but-2-ene was reacted with o-nitrophenol to yield 2-but-1-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-chloromethyl-2-pyrrolidone to form the corresponding N-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: C(OC([NH:8][CH:9]([P:17]([CH:22]([NH:30]C(OC(C)(C)C)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[O:18]CC)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.CO.C1(C)C=CC=CC=1.[ClH:47]>>[ClH:47].[NH2:8][CH:9]([P:17]([CH:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:18])[OH:21])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(=O)(C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(Cc1ccccc1)P(=O)(O)C(N)Cc1ccccc1
Yield: 93 %

Procedure:
A solution of the bisalkylated phosphinic acid ester 10 (170 mg, 0.32 mmol) in 37% aqueous hydrochloric acid (20 ml) is heated to a temperature of about 100° C. for 6 hours. After concentration of the reaction solution under reduced pressure and repeated coevaporation with methanol and toluene, the phosphinic acid hydrochloride 16 (101 mg, 93% of theory) is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([F:15])[C:3]=1[CH:4]=[O:5].[CH2:16]([C:21]1[CH:26]=[CH:25][C:24](OB(O)O)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[F-].[Cs+].COC(C)(C)C>C(COC)OC.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.O>[F:15][C:6]1[C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)ccc(OC(F)(F)F)c1F
Reactant: CCCCCc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: COCCOC
Solvent: O
Product: CCCCCc1ccc(-c2ccc(OC(F)(F)F)c(F)c2C=O)cc1

Procedure:
A mixture of 98 mmol of 2-bromo-6-fluoro-5-trifluoromethoxybenzaldehyde (Example 1), 112 mmol of 4-pentylphenylboric acid, 225 mmol of cesium fluoride (anhydrous) and 3.4 mmol of tetrakis(triphenylphosphine)palladium(0) in 480 ml of dimethoxyethane is heated to boiling until the reaction is complete. After cooling, the reaction mixture is admixed with tert-butyl methyl ether and water. The organic phase is washed with water and saturated NaCl solution and dried over sodium sulfate, and the solvents are removed under reduced pressure. After chromatographic purification of the crude product (silica gel, heptane/ethyl acetate 9:1), followed by recrystallization from heptane, 3-fluoro-4′-pentyl-4-(trifluoromethoxy)biphenyl-2-carbaldehyde is obtained in the form of colorless crystals. From this, the reaction sequence described in DE-A-101 01 020 (oxidation to the carboxylic acid, conversion to the acid chloride, intramolecular Friedel-Crafts reaction, reduction with triethylsilane) provides 1-fluoro-7-pentyl-2-(trifluoromethoxy)fluorene which, according to DE-A-101 01 020, finds use as a component of nematic or smectic liquid crystal mixtures.