Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH2:19](Cl)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCC=Cc1ccccc1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](NCC=Cc1ccccc1)c1ccccc1
Yield: 46.5 %

Procedure:
To a solution of (S)-α-methylbenzylamine (1) (0.500 g, 4.13 mmol) in toluene (20 ml) were added N-ethyldiisopropylamine (0.719 ml, 4.13 mmol) and cinnamyl chloride (0.575 ml, 4.13 mmol). The mixture was refluxed overnight, after which the toluene was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (30 ml) and the organic layer was washed with brine (30 ml), dried (magnesium suphate) and removed under reduced pressure to afford a yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:4) to give the title compound (4) as a colourless oil (0.456 g, 47%). δH (200 MHz; CDCl3) 7.41-7.20 (10H, m, Ph), 6.50 (1H, d, J=15.9, PhCH=CH), 6.30 (1H, dt, J=15.9 and 6.1, PhCH=CH), 3.88 (1H, q, J=6.6, PhCHCH3), 3.29 (2H, d, J=6.5, NCH2), 1.56 (1H, br s, NH), 1.42 (3H, d, J=6.8, PhCHCH3).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[N:8][CH:7]=[C:6]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>C(Cl)Cl>[Cl:3][C:4]1[N:9]=[N:8][CH:7]=[C:6]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:14])[CH:5]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(Nc1cnnc(Cl)c1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(Nc1cnnc(Cl)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[(6-chloropyridazin-4-yl)amino]-2-methylpropanoic acid dihydrochloride I-21b (1.23 g, 4.26 mmol), HOBT (0.979 g, 6.39 mmol), EDC (1.226 g, 6.39 mmol), and trifluoroethyl amine hydrochloride (0.866 g, 6.39 mmol) were added to DCM (20.0 ml) followed by the addition of TEA (29.7 ml, 213 mmol). The reaction was allowed to stir at room temperature for 17 hrs. The reaction was then diluted with DCM, washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and concentrated in vacuo to an oil. Purification on Biotage Normal Phase system (DCM:MeOH, 0-8% B) to afford the product I-21 as a solid. The solid was dried under vacuum (295 mg, 22.3%). LRMS (ESI) m/z 297.0 [(M+H)+; calcd for C10H12ClF3N4O: 297.0].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nn[nH]n2)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1

Procedure:
A solution of 5-(4-methylphenyl)-2H-tetrazole (W. G. Finnegan, R. A. Henry, R. Lofquist J. Am. Chem. Soc. 1958, 80, 3908.) (19.9 g, 0.12 mol), t-butanol (19.5 g, 0.26 mol) and concentrated sulfuric acid (5.84 g, 0.06 mol) in trifluoroacetic acid (122 mL) was stirred at room temperature (3 h) and then diluted with ethyl acetate (250 mL). The mixture was washed sequentially with water (2×50 mL), 10% aqueous sodium hydroxide until washings were basic, water (2×30 mL), and then dried over sodium sulfate (Na2SO4) and filtered. Following removal of the solvents in vacuo, the resultant oil was purified by HPLC on silica gel eluting with 20:1 mixture of hexanes-ethyl acetate to provide 17.5 g of 5-(4-methylphenyl)-2-(1,1-dimethylethyl)-2H-tetrazole as a clear oil, bp. 120°-122° C. (0.3 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]([N:12]=[C:13]=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17]/[C:18](/[C:25]([F:28])([F:27])[F:26])=[CH:19]\[C:20](OCC)=[O:21]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]([N:12]2[C:20](=[O:21])[CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[NH:17][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)c2c1OCC2=O
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=C1COc2c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)ccc(Cl)c21

Procedure:
By the method of Example 1, Step G, 2.10 g (0.010 mole) of 4-chloro-2,3-dihydrobenzofuran-3-on-7-yl isocyanate is reacted with 0.40 g (0.010 mole) of sodium hydride and 1.83 g (0.010 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate, yielding 3-(4-chloro-2,3-dihydrobenzofuran-3-on-7-yl)-6-trifluoromethyluracil. This product is further reacted with 1.38 g (0.010 mole) of potassium carbonate and 2.80 g (0.020 mole) of methyl iodide, yielding 3-(4-chloro-2,3-dihydrobenzofuran-3-on-7-yl)-1-methyl-6-trifluoromethyluracil (Compound 30).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[O:12][CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15].CO.[OH-].[Na+].Cl>O>[NH2:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[C:5]([O:12][CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])[CH:6]=1
Reactant: CCN(CC)C(=O)COc1cc(N)c(Cl)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)COc1cc(N)c(Cl)cc1C(=O)O
Temperature: 60 °C
Yield: 0.1 %

Procedure:
A solution of the ester (7.87 g, 25 mole) in water (70 g) containing methanol (40 g) was treated with 50% sodium hydroxide (10 g) and heated to 60° C. for 30 minutes. The mixture was neutralized with 3N HCl solution until a precipitate formed (pH~3). The solid was filtered, washed with water, air dried, and recrystallized from 2-propanol to afford (2 crops) 5.12 g (68%) of the title compound as fine colorless needles; mp 186.5°-188.0° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[N:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[N:15][C:10]([N:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:11][CH:12]=2)=[O:17])[CH2:23][CH2:22]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)nc3)CC2)c(C)c1
Yield: 42 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 4 and (6-bromopyridin-3-yl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 1, the title compound (180 mg) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[OH:21])[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH2:27](Br)[C:28]1C=CC=[CH:30][CH:29]=1>CS(C)=O>[CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[O:21][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC1=C(OCCCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.2 %

Procedure:
Under an argon atmosphere, 3-O-butylglyceryl ascorbic acid (3.06 g) obtained in Example 6 was stirred in DMSO (10 mL), and further, sodium hydrogen carbonate (0.84 g) was added. To the mixture, benzyl bromide (2.06 g) was added and the mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 3.52 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:50/3/0.3), and concentration was performed under reduced pressure to obtain 3-O-butylglyceryl-2-O-butyl ascorbic acid (0.95 g).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[F:31])[C:8]([NH:10][C:11]1[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[F:31])[C:8]([NH:10][C:11]1[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])#[N:2]
Reactant: N#C[Cu]
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(Br)c2)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(C#N)c2)cc1
Temperature: 200 °C
Reaction time: 20 h
Yield: 30.7 %

Procedure:
CuCN (606 mg, 6.77 mmol) was dissolved in NMP (25 mL) and the solution was heated to 200° C. for 45 min. To this stirring solution was added N1-(3-bromo-4-fluorobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (700 mg, 2.26 mmol) and stirring continued for 20 h. The solution was then cooled to room temperature, diluted with ethyl acetate and washed once with 1 N ammonium hydroxide, twice with 1 N HCl and once with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed with 10% ethyl acetate/dichloromethane to give 270 mg (44%) of off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11](OS(C(F)(F)F)(=O)=O)[C:9]=2[N:10]=1)(=[O:4])=[O:3].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[N:10]=1)(=[O:3])=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
A mixture of 253 mg of methyl 2-(methylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate 5 (example 2), 110 mg of benzeneboronic acid, 392 mg of caesium carbonate and 49 mg of dichloropalladium(II)bis(diphenylphosphino)ferocene in 3.5 ml of toluene is heated at 90° C. for 30 min. The mixture is cooled and poured into water. The aqueous phase is extracted three times with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum. The residue is purified on 25 g of silica, elution being carried out with dichloromethane, so as to obtain 145 mg of methyl 2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate in the form of a beige solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:21]=2)[C:16]([CH3:30])([CH3:29])[CH2:15]1.N#N.C(N(CC)CC)C>CO.[Pd]>[CH3:29][C:16]1([CH3:30])[C:17]2[C:22](=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[N:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=3)[N:8]=[C:7]([CH3:12])[C:6]=2[CH3:13])[CH2:15]1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(N4CCOCC4)cc32)c1C
Agent: [Pd]
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nc2ccccc2c(N2CC(C)(C)c3ccc(N4CCOCC4)cc32)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(1-(6-chloro-2,3-dimethylquinolin-4-yl)-3,3-dimethylindolin-6-yl)morpholine (10 mg, 0.024 mmol) in MeOH (3 mL) was purged with N2. After the mixture was purged a catalytical amount of triethylamine and Pd/C (0.003 g, 0.002 mmol) were added. The resulting mixture was stirred at rt for 2 h under a hydrogen atmosphere. After this time the reaction mixture was filtered through a pad of Celite™ and the solvent was evaporated in vacuo to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethylquinoline. 1H NMR (500 MHz, chloroform-d) δ ppm 8.06 (1H, br. s.), 7.73 (1H, d, J=8.3 Hz), 7.58 (1H, t, J=7.6 Hz), 7.33 (1H, t, J=7.6 Hz), 6.99 (1H, d, J=8.1 Hz), 6.23 (1H, d, J=7.1 Hz), 5.45 (1H, s), 3.63 (6H, m), 2.86 (4H, m), 1.43 (6H, m). Mass Spectrum (ESI) m/e=388 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:29])[C:20]=2[CH:26]=1)[CH3:2]
Reactant: CCn1c(-c2ccc3c(c2)NC(=O)CO3)c(C#N)c2ccc(OC)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2ccc3c(c2)N(C)C(=O)CO3)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BH, is combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) is added. This is stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) is added. This is stirred at room temperature for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (16 mg, 76%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:22][CH2:23]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(C)c(N2CCN(C(=O)c3cnc(F)cc3C)CC2)cc1C
Yield: 86.9 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (162 mg) and 1-(2,4,5-trimethylphenyl)piperazine (230 mg) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (310 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:10]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])=[N:10]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(N3CCNCC3)c2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(piperazin-1-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.3 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2)=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:28]2)=[O:24]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(C(=O)OC)cc4C3)c(F)c21
Yield: 28.5 %

Procedure:
271 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 217 mg of 5-methoxycarbonylisoindoline hydrochloride, 457 mg of DBU, and 3ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 122 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17].[C-]#N.[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17]
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 40 %

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenylhydrazono) succinonitrile (0.296 g, 1 mmol), sodium cyanide (0.196 g, 4 equivalents), water (1 ml) and acetic acid (5 ml) were added successively to a tube, which was sealed and reacted at 20° C. for 40 hours. The mixture was added to saturated sodium bicarbonate solution, extracted (dichloromethane), washed (water), dried (magnesium sulfate) and evaporated to give a mixture which contained 40% of the desired title compound, NMR 3.1 (m, 2H), 4.5 (m, 1H), 5.89 (m, 1H), 6.94 (d, 1H), 7.71 (s, 2H), together with 60% of unchanged starting hydrazone.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]([CH3:26])[CH2:24]O)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Si:7]([O:6][CH2:24][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([F:16])=[N:22][CH:21]=1)[CH3:26])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(CO)c1ccc(F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (2.160 mL, 9.41 mmol) was added to a solution of 2-(6-fluoropyridin-3-yl)propan-1-ol (1.39 g, 8.96 mmol) and N,N-diisopropylethylamine (3.35 mL, 19.26 mmol) in CH2Cl2 (45 mL) at 0° C., and the resulting mixture stirred at 0° C. for 2.5 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 20% EtOAc/hexanes) to provide 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridine (1.89 g, 7.01 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=2.2 Hz, 1H), 7.65 (td, J=8.1, 2.5 Hz, 1H), 6.86 (dd, J=8.4, 2.9 Hz, 1H), 3.58-3.69 (m, 2H), 2.93 (sxt, J=6.7 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H), 0.84 (s, 9H), −0.04 (s, 3H), −0.05 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −72.06 (d, J=6.0 Hz, 1 F). m/z (ESI, +ve) 270.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:23][CH2:24][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][C:2]([CH3:16])([CH3:1])[C:3]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]1=2)=[O:26]
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(C)CCCN(C(=O)CCl)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.837 g, 3.80 mmol), pyridine (0.408 mL, 5.04 mmol) and 4-dimethylaminopyridine (14.4 mg, 0.118 mmol) were dissolved in anhydrous 1,2-Dichloroethane (9.0 mL) before adding chloroacetyl chloride (0.403 mL, 5.07 mmol). The reaction was stirred at room temperature for 3 hours, washed sequentially with 1 N HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether (6 mL×2) to yield a crude brown solid, 2-Chloro-1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone. LCMS: m/z=297.42 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].ClCl>>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Cl:21]
Reactant: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: ClCl
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)c(Cl)c1
Yield: 60 %

Procedure:
65 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-toluene and 2 parts by weight of phosphorus pentachloride were treated with chlorine gas for half an hour at 200° C. Fractional distillation gave 43.2 parts by weight (60% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzyl chloride of boiling point 135°-145° C. and refractive index nD25 : 1.5427.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([O:15][C:13]([CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(CCO)cc1

Procedure:
The hapten p-(carboxymethyl)ritodrine (Hapten E) was prepared in four steps according to FIG. 7 of the accompanying drawings, from 2-(4-hydroxyphenyl)ethanol 17. The reaction of 17 with t-butyl bromoacetate in acetonitrile in the presence of potassium carbonate at 60° C. gives 2-[4-(t-butoxycarbonylmethoxy)phenyl]ethanol 18. The oxidation of the alcohol 18 with pyridinium chlorochromate (pcc) in dichloromethane gives the 2-[4-(t-butoxycarbonylmethoxy)phenyl]ethanal 19. The ester 20, obtained by condensation of the aldehyde 19 with α-(1-aminoethyl)-4-hydroxybenzyl alcohol hydrochloride 13 in methanol in the presence of sodium cyanoborohydride and triethylamine. Deprotection of the t-butyl protecting group of the ester 20 with 4 M HCl in dioxane at room temperature gave Hapten E in moderate yield.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>>[ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][C:18]([OH:17])=[CH:19][CH:20]=2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Reactant: Oc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)cc3)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (375 mg, 1.54 mmol), 2-(4-hydroxyphenoxy)ethyl bromide (352 mg, 1.62 mmol) and NaHCO3 (265 mg, 3.16 mmol) as a near colorless powder (430 mg): mp 164-165° C.; 1H NMR (CD3OD) 1.51-1.70 (m, 2H), 1.84-2.00 (m, 3H), 2.31 (s, 3H), 2.63 (d, J=5.7 Hz, 2H), 2.94-3.12 (m, 2H), 3.44-3.70 (m, 4H), 4.26 (t, J=4.8 Hz, 2H), 6.74 (d, J=9.3 Hz, 2H), 6.82-6.96 (m, 4H), 7.07-7.14 (m, 1H); Anal. Calcd for C21H27ClFNO2 : C, 66.39; H. 7.16; N, 3.69. Found: C, 66.62; H, 6.99; N, 3.54.