Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[O:6][C:7]3[C:25](F)=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[F:29]C1C=CC=C(F)C=1C=O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[C:22]([F:29])[C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3c(F)cccc3[C@H]12)C(F)(F)F
Reactant: O=Cc1c(F)cccc1F
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3cccc(F)c3[C@H]12)C(F)(F)F
Yield: 6 %

Procedure:
Preparation according to the procedures described in Example 72 for trans-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide starting from 2,6-difluorobenzaldehyde (0.54 mL, 5 mmol) delivered the crude title compound. This compound was purified by column chromatography on silica gel with heptanes/ethyl acetate, column chromatography on silica gel with toluene/ethyl acetate=9/1 and finally crystallization from acetonitrile to yield the title compound (136 mg, 6% overall yield). Data: 1H-NMR (400 MHz, DMSO d6) 1.57-1.76 (m, 2H), 1.89-2.04 (m, 2H), 3.09-3.18 (m, 1H), 3.93 (br.d, J=14, 1H), 4.42 (d, J=10, 1H), 4.52-4.62 (m, 1H), 6.74 (dd, J=9, 3, 1H), 6.95-7.16 (m, 4H), 7.27-7.33 (m, 1H), 9.30 (d, J=9, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl-2,4-dihydroxybenzoate (10 g, 59.5 mmol) in acetone (200 mL) at 0° C. is added K2CO3 (30 g, 217 mmol), followed by benzyl bromide (7.72 mL, 65 mmol). The solution is warmed to ambient temperature and stirred for 48 h. The mixture is filtered and the solvent removed under reduced pressure. The crude oil is dissolved in EtOAc and washed with water, saturated NaHCO3, and dried over sodium sulfate. The solvent is removed under reduced pressure and the solid purified by flash chromatography using hexane/EtOAc (10:1) to afford 4-benzyloxy-2-hydroxybenzoic acid methyl ester as a white powder: 1H NMR (CDCl3) δ 10.93 (s, 1H), 7.73 (d, J=9.09 Hz, 1H), 7.42-7.33 (m, 5H), 6.53-6.49 (m, 2H), 5.07 (s, 2H), 3.90 (s, 3H); (M+H)+=259.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>ClCCl>[CH:1]1([NH:7][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][Cl:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCCCCl
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCCCl)NC1CCCCC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Dissolve cyclohexylamine (8.86 mL, 77.5 mmol) in dichloromethane (700 mL), cool to 0° C. and add 5-chloropentanoyl chloride (10 mL, 77.5 mmol). After 6 h, wash the mixture with 1N HCl and saturated aqueous sodium bicarbonate and brine, dry the organic layer over sodium sulfate and evaporate to a white solid to obtain 5-chloro-pentanoic acid cyclohexylamide: MS (EI) m/z=217 (M+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1.O>COCCOC>[NH:1]1[C:5]2=[N+:6]([O-:18])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Solvent: O
Product: [O-][n+]1cccc2cc[nH]c21
Reaction time: 1 h
Yield: 41 %

Procedure:
The commercially available 1H-pyrrolo[2,3-b]pyridine x7 (6.0 g, 50.8 mmol) is dissolved in 1,2-dimethoxyethane (50 ml). A solution of 70-75% m-chloroperbenzoic acid (17 g, 1.4 eq, 71.1 mmol) in 1,2-dimethoxyethane (40 ml) is added under cooling with cold water at a temperature below 25° C. The obtained suspension of the salt is stirred additionally for 1 h, kept overnight at −20° C. and filtered. The solid on the filter is washed with ether (2×30 ml) and air-dried. The obtained product is dissolved in a minimum of water. The pH of the solution is adjusted to 9 by the addition of aqueous K2CO3 under stirring and cooling with cold water. The formed suspension of the free N-oxide x257 is kept at +3° C. overnight and filtered. The product is washed with ice-cold water (2×10 ml) and dried over P2O5 under 1 mmHg to yield 1H-pyrrolo[2,3-b]pyridine 7-oxide x257 (3.4 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].O>C(#N)C>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4])[CH3:36]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and diethyl amine (63 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. Product was purified by column chromatography using 10% methanol in methylenechloride as eluant. 2-Diethylamino-N-[6-(2-phenyl-chroman-6-yloxy)pyridin-3-yl]acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 2.0, 10.0 Hz), 4.14 (d, 2H, J 4.9 Hz), 3.24 (k, 4H, J 7.2 Hz), 3.01-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.15 (m, 1H), 2.04-1.94 (m, 1H), 1.24 (t, 6H, J 7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24].[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:24])[CH:17]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(F)c2)n1
Temperature: 85 °C
Yield: 71 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (3.0 g, 14.66 mmol), (4-chloro-3-fluorophenyl)boronic acid (3.07 g, 17.60 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.029 g, 1.466 mmol), and cesium fluoride (4.45 g, 29.3 mmol) were comined in a flask that was sealed and purged with nitrogen. Dioxane (50 ml) and Water (10.00 ml) were added and the reaction mixture was heated at 85° C. for 18 hrs. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with saturated sodium chlride, dried over magnesium sulfate, filtered, and concentrated onto silica. The product was purified by flash chromatography (SiO2, 0-40% EtOAc:Hex gradient) to provide the title compound (3.11 g, 10.41 mmol, 71.0% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 3.85 (s, 3H), 6.72 (s, 2H), 7.49 (d, J=6.3 Hz, 1H), 7.68-7.80 (m, 2H), 7.84 (dd, J=10.8, 1.3 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −144.47, −116.07; ESIMS m/z 299 ([M+H]+).
Reaction SMILES: C(OC1[C:6](=CC=CC=1)[C:7]([O:9][C:10](=[O:21])[C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:13][C:14](=[O:16])[CH3:15])=O)(=O)C.OC(C)[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH:36]([OH:38])[CH3:37])[CH2:31][CH2:30]1>C(OCC)(=O)C>[C:14]([O:13][C:12]1[C:11](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:9][CH:7]([CH3:6])[CH2:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH:36]([O:38][C:10](=[O:9])[C:11]2[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14](=[O:16])[CH3:15])[CH3:37])[CH2:33][CH2:34]1)=[O:21])(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1ccccc1C(=O)OC(=O)c1ccccc1OC(C)=O
Reactant: CC(O)CN1CCN(CC(C)O)CC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)OC(C)CN1CCN(CC(C)OC(=O)c2ccccc2OC(C)=O)CC1
Temperature: 25 °C

Procedure:
Dissolve acetylsalicylic anhydride (17.1 g; 0.05 moles) in an apolar organic solvent represented for example by ethyl acetate; add 1,4-bis-(2-hydroxypropyl)piperazine (5.06 g; 0.025 moles) to the solution, and heat up to the boiling point until the reaction is completed. After cooling at room temperature, wash the reaction mixture with a 5 percent aqueous solution of potassium carbonate, and then with water. Anhydrify the organic phase (K2CO3), filter, and treat it with anhydrous hydrochloric acid dissolved in diethylether causing by this procedure the precipitation of the raw product that, after collection and drying, can be recrystallized from a low molecular weight alcohol.
Reaction SMILES: [N:1]([CH:4]([CH2:7][N:8]=[N+:9]=[N-:10])[CH2:5][OH:6])=[N+:2]=[N-:3].[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)(Cl)Cl>[N:1]([CH:4]([CH2:7][N:8]=[N+:9]=[N-:10])[CH2:5][O:6][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:7][N:8]=[N+:9]=[N-:10])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(CO)N=[N+]=[N-]
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NCC(COC(=O)CCCCC(=O)OCC(CN=[N+]=[N-])N=[N+]=[N-])N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
8.52 g (0.06 Mole) 2,3-diazidopropanol in 20-ml dry CCl4 is added dropwise to 5.49 g (0.03 Moles) adipyl chloride in 30-ml dry CCl4 while the temperature is held below 20° C. At the end of the addition, the cooling bath is removed and the temperature is allowed to rise to 25° C. The reaction mixture is allowed to stir at ambient temperature for 18 hours under a slow flow of nitrogen to purge HCl produced in the reaction. At the end of this period the reaction mixture is washed with H2O, dilute bicarbonate solution, and a final H2O wash. The resultant colorless solution is stripped of solvent to yield 9.8 g (83%) colorless oil nD25 1.5050, d425 1.258; infrared spectrum is consistent with the expected structure. Elemental analysis for nitrogen gives 42.01%, theoretical is 42.62%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[C:10]([Cu])#[N:11]>CN(C=O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C#N
Yield: 60 %

Procedure:
A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[C:14]([OH:16])=[O:15])([O-:3])=[O:2].Cl.[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34]N)[C:29]=2[F:36])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:18]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]3[C:9]4[CH2:8][C:7]5[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:14]([OH:16])=[O:15])[CH:6]=5)[C:10]=4[NH:34][C:30]=3[C:29]=2[F:36])=[CH:26][CH:27]=1)[CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCc2cc(C(=O)O)c([N+](=O)[O-])cc21
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2cc([N+](=O)[O-])c(C(=O)O)cc2C4)cc1
Temperature: 105 °C
Yield: 41.2 %

Procedure:
A sealable reaction vial was charged with 6-nitro-1-oxo-indan-5-carboxylic acid (26 mg, 0.12 mmol), (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (example 78, step 1) (25 mg, 0.12 mmol), zinc (II) chloride (24 mg, 0.18 mmol), and acetic acid (1.5 mL), sealed, and heated to 105° C. overnight. Reaction was then cooled to RT, concentrated in vacuo, and purified by UV-triggered HPLC to afford 22 mg (41%) of 7-(4-Butyl-phenyl)-6-fluoro-3-nitro-5,10-dihydro-indeno[1,2-b]indole-2-carboxylic acid; LC/MS calculated for [M+H]+ C26H21FN2O4: 445.1, found: 445.1.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[O-].[K+].CO.[CH2:15]([S-])CCCCCCC.[K+]>>[CH3:15][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS
Reactant: CCCCCCCC[S-]
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCSC
Reaction time: 15 h
Yield: 92 %

Procedure:
In a 0.3 liter stainless steel stirred autoclave, 37.9 g (0.26 mole) of n-oct-1-yl mercaptan and 20.3 g (0.29 mole) of potassium methylate were dissolved in 120 ml (3.0 moles) of methanol at 20° C., the resulting potassium octane-1-thiolate solution was heated from 20° to 150° C. in the course of 20 minutes under a carbon monoxide pressure of 300 bar, and the mixture was then kept at this temperature for 15 hours. The carbon monoxide consumed during the reaction was replaced continuously, and the pressure was kept constant at 300 bar. The mixture which emerged from the reactor was distilled under atmospheric pressure, and a methanol/methyl formate mixture was separated off and 38.2 g (92% of theory) of n-octyl methyl sulfide was obtained at 110° C./34 mbar.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[NH:14][C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(CC)c2cccc(C)c21
Temperature: 0 °C
Reaction time: 3 h
Yield: 124.5 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (1.0 g) and 60% sodium hydride (120 mg) in N,N-dimethylformamide was stirred at 0° C. for 1 hour and at room temperature for 3 hours. To the resultant mixture was added dropwise ethyl bromoacetate (476 mg) under cooling at 0-5° C. in an ice-bath. The mixture was stirred for 5.5 hours under the same conditions. The reaction mixture was poured into 0.1N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water twice, saturated aqueous sodium bicarbonate and brine successively and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford (3RS)-3-benzyloxycarbonylamino-5-ethyl-2,3-dihydro-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.55 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])=[O:5])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)=[CH:28][CH:27]=1.S([O-])([O-])(=O)=O.[Mg+2].[Na]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:35][CH2:34][CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Reactant: O=CCCCc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na]
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Temperature: -10 °C
Yield: 50.3 %

Procedure:
To a dry flask were added 5.0 g (14.9 mmol) of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester, 1.98 g (13.5 mmol) of 4-(pyridin-4-yl)butyraldehyde (diluted with 0.5 mL of CDCl3), 8.12 g (67.7 mmol) of anhydrous magnesium sulfate, and a magnetic stirring bar. The flask was purged with nitrogen, cooled to -10° C., and stirred as 11.5 mL of dry CDCl3 was introduced gradually by syringe. The mixture was stirred under nitrogen for about 20 minutes. Next, the septum was removed, and 670 mg (17.6 mmol) of sodium borohyrdide was added rapidly. The septum was immediately replaced, and the system was again purged with nitrogen. The mixture was stirred under nitrogen at about -5° C. as 10 mL of dry methanol was added gradually by syringe. After a few minutes at this temperature, the reaction was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with a gradient of 4-9% methanol in methylene chloride; repeated using 5-15% methanol in methylene chloride) to give the title compound (3.19 g). 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB--NH3 /CI): m/e=470.4 (M+H). An additional 1.91 g of less pure material was also isolated.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCBr
Product: CCCCCCCCOc1ccccc1

Procedure:
effecting reaction between phenol and a-bromo octane in the presence of an aqueous basic solution and a phase transfer catalyst to form n-octylphenyl ether,
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:22]=[C:23]([C:27]3([C:33]([OH:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)[CH:14]=1.[CH2:36](O)[CH3:37]>>[CH2:36]([O:34][C:33]([C:27]1([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:15]3[CH:14]=[C:13]([NH:12][CH2:11][CH2:10][C:4]4[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=4[Cl:2])[N:18]=[C:17]([O:19][CH3:20])[N:16]=3)[CH:22]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)=[O:35])[CH3:37]
Reactant: CCO
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Agent: Cl
Product: CCOC(=O)C1(c2cccc(-c3cc(NCCc4ccc(Cl)cc4Cl)nc(OC)n3)c2)CCOCC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 20 μL, 0.08 mmol) is added to a solution of 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid [20 mg, 0.04 mmol, Example 80(a)] in ethyl alcohol (4 mL) and the reaction mixture is stirred overnight at 75° C. The reaction is cooled to room temperature, quenched with water, extracted twice with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid ethyl ester [16 mg, Example 80(c)]. LCMS: RT=2.74 minutes; MS: 530, 532 (M+H); 1H NMR (300 MHz, CDCl3): □8.05 (1H, s), 7.9 (1H, d, J=3.5 Hz), 7.4-7.55 (3H, m), 7.2 (2H, s), 6.4 (1H, s), 5 (1H, b), 4.18 (2H, q, J=2 Hz), 4.05 (3H, s), 3.98 (2H, m), 3.75 (2H, b), 3.65 (2H, t, J=3.5 Hz), 3.1 (2H, t, J=2 Hz), 2.6 (2H, d, J=4 Hz), 2.1 (2H, m), 1.2 (3H, t, J=2 Hz). IC50=223 nM
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:32])[C:27](=[O:31])[CH2:28][O:29][CH3:30])=[N:24][CH:25]=1>>[CH3:30][O:29][CH2:28][C:27]([N:26]([CH3:32])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)=[O:31]
Reactant: COCC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-acetyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide. LCMS calcd for C20H17F3N4O4 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[C:24]([OH:27])(=[S:26])[CH3:25].CC(N=NC(C#N)(C)C)(C#N)C.C1CCCCC=1>O1CCOCC1>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:14](=[O:22])[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:26][C:24](=[O:27])[CH3:25])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: CC(=O)SCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of ((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester (250 mg, 0.78 mmol), thioacetic acid (564 μl, 7.8 mmol) at 75° C. in degassed dioxane was added AIBN (129 mg, 0.78 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was cooled to 0° C. and an excess of cyclohexene was added under stirring, the latter being maintained for 20 mn. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was rinsed more times with hexane to afford the desired adduct.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]([F:14])([F:13])[C:8](OCC)=[O:9]>>[Br:6][C:7]([F:14])([F:13])[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C1CCNC1
Product: O=C(N1CCCC1)C(F)(F)Br
Reaction time: 1 h

Procedure:
Pyrrolidine (7.7 g, 108 mmol) was added to ethyl bromodifluoroacetate (20.2 g, 100 mmol) at 30° C. The mixture was stirred for 60 min; then all volatiles were removed under reduced pressure and the residue (24.0 g, >90% purity by NMR) was used in subsequent steps without further purification.