Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[C:12]([O:20][CH3:21])[C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1)([OH:9])=O.C(N(CC)CC)C.[CH2:29]([O:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:31][CH3:32]>CN(C)C=O.O1CCCC1.ClCCl>[CH2:29]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:7]([C:10]1[CH:11]=[C:12]([O:20][CH3:21])[C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1)=[O:9])[CH2:30][CH2:31][CH3:32]
Reactant: COC(=O)c1ncc(C(=O)O)cc1OC
Reactant: CCCCOCCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOCCCNC(=O)c1cnc(C(=O)OC)c(OC)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.7 ml of oxalyl chloride (20 mmol), and also 2 drops of N,N-dimethylformamide, dissolved in tetrahydrofuran, were added dropwise, at 10° C. and while stirring, to 2.1 g (10 mmol) of methyl 5-carboxy-3-methoxypyridine-2-carboxylate in 100 ml of anhydrous tetrahydrofuran and the reaction mixture was stirred at 10° C. for 30 min and at 20° C. for 1 h. It was then concentrated and the residue was dissolved in dichloromethane; 6.8 ml (50 mmol) of triethylamine, and then 1.3 g (1.5 ml, 10 mmol) of 3-butoxypropylamine, dissolved in dichloromethane, were added, at 0° C., to this solution.
Reaction SMILES: [CH2:1]([C:4]([CH3:10])([CH:8]=[CH2:9])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([C:4]([CH3:10])([CH:8]=[CH2:9])[CH:5]([OH:7])[CH3:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C)(C=C)C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCC(C)(C=C)C(C)O

Procedure:
In an analogous manner to that of Example 7, 27.6 g (0.2 moles) 3-allyl-3-methyl-pent-4-en-2-one (according to Example 3) are reduced with 2.2 g (0.058 moles) LiAlH4.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH2:15]([NH:17][CH2:18]C)C>O>[CH3:15][N:17]([CH3:18])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CCNCC
Solvent: ClCCl
Solvent: O
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and diethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetra-fluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC#N)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc(C(C)C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 250 ml flask, 4-isopropylphenylacetonitrile 8.00 g (50.2 mmol) was dissolved in tetrahydrofuran (150 ml) under a nitrogen atmosphere. The solution was cooled to −78° C. and lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 52.8 ml (52.8 mmol) added. The resulting mixture was stirred at −78° C. for 1 hour. To this reaction mixture was added iodomethane 3.29 ml (52.8 mmol). The resulting mixture was slowly allowed to warm to ambient temperature over 16 hours then quenched with 0.2M hydrochloric acid and extracted twice with diethyl ether. The organic fractions were combined, dried (MgSO4) and concentrated under vacuo. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave 6.32 g (73%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([NH:13][C:14]([C:16]2[C:17]([CH3:29])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[N:20][CH:21]=2)=[O:15])[CH:4]=1)#[N:2].[Si]([N:34]=[N+:35]=[N-:36])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([NH:13][C:14]([C:16]1[C:17]([CH3:29])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[N:20][CH:21]=1)=[O:15])[CH:4]=[C:3]2[C:1]1[NH:36][N:35]=[N:34][N:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C#N)c2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(-c2nnn[nH]2)c2cc(F)ccc21
Yield: 74.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-cyano-5-fluoro-indol-1-yl)-amide (120 mg, 0.31 mmol), TMSN3 (62 μL, 0.465 mmol), and TBAF (0.155 μL, 0.155 mmol, 1 M in THF) in toluene (3 mL) is heated at 80° C. for 18 h. The mixture is cooled, diluted with EtOAc, and washed with 1 M HCl. The organic layer is extracted with Na2CO3. The aqueous layer is acidified to pH ˜3 with 3 N aqueous HCl, extracted with EtOAc The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [5-fluoro-3-(1H-tetrazol-5-yl)-indol-1-yl]-amide (100 mg, 75%). MS: 433 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.81 (s, 3H), 7.28 (m, 1H), 7.47 (m, 1H), 7.67 (m, 1H), 7.73 (m, 1H), 8.01 (m, 1H), 8.21 (m, 1H), 8.33 (m, 1H), 8.36 (s, 1H), 9.33 (s, 1H). IC50=5 nM.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Yield: 86.8 %

Procedure:
Cyclohexylamine (0.67 mL, 5.85 mmol) was added to a solution of Compound 6 (1.0 g, 2.92 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystalized by ether to yield 1.0 g (87%) of white solids. M.P. 168° C. 1H NMR (DMSO-d6): δ 1.26 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.89 (m, 2H), 3.88 (m, 1H), 5.51 (s, 2H), 7.13 (m, 2H), 7.25 (m, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.70 (t, J=8.4 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 10.35 (s, 1H), 17.66 (s, 1H), EIMS m/z 395 (M+1), 417 (M+23). Anal. (C23H23FN2O3) C, H, N.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH3:31])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:32])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)[CH3:31]
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1c(-c2cccc3cc(C(C)=CC(=O)O)oc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3), δ: 7.65 (d, J=7.5 Hz, 1H, Ar—H), 7.56 (d, J=7.7 Hz, 1H, Ar—H), 7.33 (d, J=2.0 Hz, 1H, Ar—H), 7.29 (t, J=7.6 Hz, 1H, Ar—H), 7.16 (d, J=2.0 Hz, 1H, Ar—H), 7.11 (s, 1H, furan-H), 6.60 (s, 1H, C═C—H), 3.43 (m, 3H, CH3—CH—CH3, O—CH2—CH3), 2.95 (m, 1H, CH3—CH—CH3), 2.57 (s, 3H, C═C—CH3), 1.31 (d, J=6.9 Hz, 12H, CH3—CH—CH3), 0.97 (t, J=7.0 Hz, 3H, O—CH2—CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C)C=O>[CH2:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:18]
Reactant: CCI
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of 3,4-difluoro-phenol (10 g, 77 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (20 g, 145 mmol) and iodoethane (50 g, 320 mmol, Aldrich). The reaction mixture was heated at refluxing for 48 h. The crude was cooled to room temperature and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:8) to give 4-ethoxy-1,2-difluoro-benzene as colorless oil (Yield 11 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:24](COCC[Si](C)(C)C)[C:23]4[C:22](=[O:33])[N:21]([CH2:34][CH2:35][CH3:36])[C:20]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:19][C:18]=4[N:17]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1.Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[NH:24][C:23]4[C:22](=[O:33])[N:21]([CH2:34][CH2:35][CH3:36])[C:20]([N:37]5[CH2:38][CH2:39][CH2:40][CH2:41]5)=[N:19][C:18]=4[N:17]=3)[CH:13]=[N:12]2)=[CH:6][CH:7]=1
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)[nH]c2c1=O
Temperature: 85 °C
Yield: 109.6 %

Procedure:
A mixture of 8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.025 g, 0.043 mmol), 2N HCl (0.5 ml), ethanol (2 ml) was heated at 85° C. for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with n-pentane to obtain pure 8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one (0.021 g, quantitative) as yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.O=[CH:16][CH2:17][C:18]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:16][CH2:17][C:18]3([C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: O=CCC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC2CCN(CCC3(C(=O)OCc4ccccc4)CCCCC3)CC2)nc1
Yield: 86.3 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (277 mg) and benzyl 1-(2-oxoethyl)cyclohexanecarboxylate (360 mg) in tetrahydrofuran (15 mL) was added acetic acid (207 mg) and triacetoxyborohydride (731 mg) at room temperature. After stiring the solution for 18 hours, saturated aqueous sodium bicarbonate solution was added thereto and it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) to give the title compound (520 mg).
Reaction SMILES: [Cl:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]2[B:6]([OH:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=[O:22])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:13]([CH:14]=[O:22])=[CH:12][C:5]2[B:6]([OH:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1Cl)C(C)(C)OB2O
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2cc(C=O)c(Cl)cc21
Temperature: 25 °C
Yield: 531.2 %

Procedure:
To a solution of 5-chloro-3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (540 mg, 2.57 mmol) in CCl4 (30 mL) at rt was added benzoyl peroxide (62 mg, 0.26 mmol) followed by NBS (915 mg, 5.14 mmol). The reaction mixture was refluxed for 16 h, cooled to rt and treated with Na2CO3. The aqueous layer was acidified with 3 N HCl to pH of 3 and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with DCM-MeOH (20:1) to give 5-chloro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (310 mg; yield 53.8%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.41 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H), 1.50 (s, 6H) ppm; MS: m/z=224.9 (M+1, ESI+).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5](Cl)[N:4]=1.[CH3:13][OH:14]>>[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([O:14][CH3:13])[N:4]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(N)n1

Procedure:
1.65 g (0.0717 mol; 2 equivalents (eq)) of sodium are dissolved in 100 cm3 of methanol. 6.2 g (35.7 mmol) of 2-amino-6-chloro-3-nitropyridine are added and the solution is brought to reflux for 8h. The methanol is evaporated under reduced pressure and the residue is taken up in the minimum amount of water (20 cm3). The solution is extracted with 100 cm3 of ethyl ether. The ether phase is washed with water (20 cm3), separated by settling, dried over MgSO4, decolored with animal charcoal and evaporated on a rotary evaporator to give a 1 st crop. The aqueous phase is extracted under the same conditions with 2 times 50 cm3 of ethyl acetate, giving a 2nd and 3rd crop.
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl[C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>C(#N)C.CN(C=O)C>[CH2:49]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:9]=[C:8]([CH3:25])[C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:27])[CH3:26])=[C:12]([CH3:13])[CH:11]=2)([OH:24])[C:15]1=[O:23])[C:48]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:47]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Yield: 81.1 %

Procedure:
Using a method similar to Preparation 17 with 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (3.83 g, 10 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (3.5 ml, 12 mmol) and 2-chlorobenzyl bromide (1.56 mL, 12 mmol) in acetonitrile/DMF (60 mL/20 mL) gives 5.9 g of a crude yellow gum. Purify by flash chromatography (CH2Cl2 to 10% EtOAc/CH2Cl2) gives 3.84 g (76%) of the title compound as a white solid. Mp 147.1° C. MS (ES): m/z=490 (M+1−H2O); 1H NMR(DMSO-d6): δ7.52 (dd, J=1.7, 1.4 Hz, J=7.7, 7.4 Hz, 1H), 7.37-7.14 (m, 5H), 7.05 (t, J=7.7 Hz, 1H), 6.93 (s, 2H), 6.86 (d, J=7.7 Hz, 1H), 6.73 (s, 1H), 4.96 (abq, 2H), 2.11 (s, 6H), 0.98 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][N:11]=[C:10]([CH:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[C:14]=2[CH:15]=1
Reactant: CC(=O)N1CCC(c2noc3ccc(F)cc23)CC1
Agent: Cl
Product: Fc1ccc2onc(C3CCNCC3)c2c1
Yield: 83 %

Procedure:
A mixture of 17.5 g of 3-(1-acetyl-4-piperidyl)-5-fluoro-1,2-benzisoxazole and 110 ml of 6N hydrochloric acid was stirred under reflux for 6 hrs. After standing at ambient temperature for ca 12 hrs, a solid was collected, washed with acetone and dried to yield 14.2 g (83%) of product as the hydrochloride salt, mp 297°-299°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][C:5]2[NH:11][C:10](=[S:40])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1

Procedure:
7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4benzodiazepin-2-thione (IIj) was prepared by reacting 0.0011 moles of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ij) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=508.
Reaction SMILES: C(C1C=[C:5]([NH:9][C:10]2[N:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:13]([F:25])=[C:12]([CH3:26])[C:11]=2[F:27])C=CC=1)#N.IC.[H-].[Na+].[C:32](#[N:34])[CH3:33]>>[C:32]([C:33]1[CH:10]=[C:11]([CH2:5][NH:9][C:10]2[N:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:13]([F:25])=[C:12]([CH3:26])[C:11]=2[F:27])[CH:12]=[CH:13][CH:14]=1)#[N:34]
Reactant: CC#N
Reactant: Cc1c(F)c(Nc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1c(F)c(NCc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1F
Reaction time: 18 h

Procedure:
To 3-[(6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile (0.10 g, 0.28 mmol) in acetonitrile (10 mL) was added iodomethane (0.20 g, 1.4 mmol) and sodium hydride (0.055 g, 1.4 mmol). After stirring for 18 hours the reaction was partitioned with water and ethyl acetate. The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo. Chromatography of the residue on silica gel with ethyl acetate/hexane (1/3) as eluent gave 3-[(6-(3-cyanophenyl)methylamino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile; NMR (CDCl3) 7.4 (m,5), 7.25 (m,1), 7.1 (m,2), 3.25 (s,3), 2.3 (s,3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].COCCOC.[BH4-].[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9]
Reactant: O=Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
A solution of 90 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzaldehyde in 300 parts by volume of ethylene glycol dimethyl ether was added dropwise to a suspension of 5.7 parts by weight of sodium borohydride in 200 parts by volume of ethylene glycol dimethyl ether at 0° C. The reaction mixture was further stirred for 12 hours at room temperature, 500 parts by volume of water were added and the mixture was acidified with 10% strength sulfuric acid. It was then extracted with ether, the organic phase was dried with magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. Fractional distillation of the residue gave 80 parts by weight (89% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzyl alcohol (compound No. 3) of boiling point 140°-145° C./0.1 bar and refractive index nD25 : 1.5330.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:25][C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.O>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:25][C:15]2[N:16]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Heat a mixture of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (5 g, 15.3 mmol) in DMF (25 ml) to 40° C. Add cesium carbonate (10.4 g, 32.4 mmol) and 2-bromomethylpyridine hydrobromide (4.05 g, 16 mmol). Stir the mixture at 40° C. for 24 h. Add the mixture to water (250 mL) and stir for 1 h. Filter the solids and dry the collected material under vacuum. Add the solid to ethanol (25 mL) and reflux for 30 min. Cool the mixture to 22° C. and filter. Dry the solid under vacuum to constant weight to provide 4.8 g (75%) of the title compound. MS (m/z): 419 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][N:34]=1.[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51]O)=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1>[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51][O:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][N:34]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: Oc1noc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccccc12
Temperature: 5 °C
Yield: 68.9 %

Procedure:
To a solution of triphenylphosphine (0.95 g) in tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.63 g) with stirring at 5° C., then stirred at the same temperature for 15 minutes. To a reaction mixture, 3-hydroxy-1,2-benzisoxazole (0.45 g) was added and stirred for 15 minutes, then N-t-butoxycarbonyl ethanolamine (0.53 g) was added and the mixture stirred at room temperature for 24 hour. The solvent was evaporated under reduced pressure and residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.63 g, 68%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:4]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: CC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B, at 50° C. for 30 hours. The evaporation residue is purified by silica-gel chromatography.