Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=1)[CH3:17].CCOCC>ClCC(Cl)(Cl)Cl>[CH2:16]([C:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH:21]=[CH:22][C:23]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])[CH3:17]
Reactant: CCc1cccc(CC)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCc1ccc(C(=O)c2ccccc2C(=O)O)c(CC)c1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a cooled mixture of phthalic anhydride (50 g, 0.34 mol) and aluminum chloride (99 g) in tetrachloroethane (300 mL) was added dropwise 1,3-diethylbenzene (50 g) over 11/4 hours. The mixture was stirred in an ice bath for 30 minutes, additional tetrachloroethane was added, and the mixture was stirred for 2 hours. The reaction mixture was poured into concentrated HCl/ice (1 L), ether (500 mL) was added and the mixture was filtered. The organic layer was separated, washed with saturated Na2CO3 (6×), the basic layer was extracted with CH2Cl2 and the CH2Cl2 layer was extracted with 2N NaOH and the 2N NaOH layer was acidified. The basic layer was acidified with aqueous HCl, this acidic layer was combined with the above acidified 2N NaOH layer and the mixture was extracted with ether. The CH2Cl2 layer and the ether layer were combined and concentrated in vacuo. The residue was slurried with water, filtered and rinsed with hexane to afford 88.8 g (93%) of 2-(2,4-diethylbenzoyl)benzoic acid, m.p. 115°-118° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5](Cl)=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)=[N:4][C:3]=1[CH3:13]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(C)c1Br
Reactant: Nc1ccc(CCO)cc1
Product: Cc1nc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c(C)c1Br

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-bromo-6-chloro-2,4-dimethyl-5-nitropyridine (step 2) and 4-aminophenylethyl alcohol.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:22]([CH3:24])[CH3:23])[N:16]=[C:17]([CH2:19][O:20][CH3:21])[N:18]=1)[N:7]=3.B1([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>COCCOC.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH:37]=[C:36]([C:2]2[CH:26]=[CH:25][C:5]3[C:6]4[N:10]([CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:9]=[C:8]([C:14]2[N:15]([CH:22]([CH3:24])[CH3:23])[N:16]=[C:17]([CH2:19][O:20][CH3:21])[N:18]=2)[N:7]=4)[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Yield: 71.7 %

Procedure:
8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (250 mg, 0.60 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (370 mg, 1.20 mmol), cesium carbonate (585 mg, 1.79 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (ii) dichloride, dichloromethane (24 mg, 0.03 mmol) were suspended in DME (4.0 mL), IMS (1.3 mL) and water (0.68 mL) and the reaction mixture purged with argon. The reaction mixture was heated using microwave irradiation in a sealed tube at 140° C. for 20 min. The reaction mixture was washed with water, extracted with DCM (2×15 mL) and the combined organics were washed with brine, dried (Na2SO4) then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 5% methanol in DCM) to yield 4-[2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a brown foam (224 mg, 72%). LCMS: RT=5.08 min, [M+H]+=521
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[S:11][CH:12]=2)=[C:6]([CH3:17])[CH:5]=[N:4]1)[CH3:2].[OH-].[K+]>C1COCC1.O>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=2)=[C:6]([CH3:17])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C)c1-c1csc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc(C)c1-c1csc(C(=O)O)c1
Temperature: 50 °C
Yield: 94 %

Procedure:
To a solution of methyl 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (270 mg, 1.08 mmol) in THF/H2O (2 mL/0.4 mL) was added KOH (303 mg, 1.79 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give the crude acid (240 mg), which was used directly in the next step without further purification: LC-MS m/z=237 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[C:9]([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Product: CCCC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 286 mg (4.2 mmol) of pentyne, 60 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:5].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.Cl>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]1[CH2:26][CH2:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=2)[CH2:29][CH2:28]1)([O-:15])=[O:14]
Reactant: O=C(CCBr)Nc1ccccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Product: O=C(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)Nc1ccccc1[N+](=O)[O-]

Procedure:
The compound was prepared from 3-bromo-N-(2-nitrophenyl)propionamide and 1-(3-trifluoromethylphenyl)piperazine according to the method described in J. Med. Chem. 33, 2970 (1990). Monohydrochloride salt. M.p. 185°-188° C.
Reaction SMILES: ClC1C=C([C@@H](O)CN(CCC2C=CC([C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[C:28](C)[C:27]=3C)=CC=2)C(=O)OC(C)(C)C)C=CC=1.OO.Cl([O-])=[O:40].[Na+]>C(#N)C.C(OCC)(=O)C>[C:32]([OH:33])(=[O:40])[C:29]1[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1c(C=O)ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1C
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4′-formyl-2′,3′-dimethyl-1,1′-biphenyl-4-yl)ethyl)carbamate in acetonitrile (2.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.3 ml) was added 30% hydrogen peroxide solution (60 μl) and 80% sodium chlorite (128 mg) below 10° C. The reaction mixture was stirred at 40° C. for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.0 ml) was added 4N hydrochloride in dioxane (1.18 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,3-dimethyl-1,1′-biphenyl-4-carboxylic acid hydrochloride (140 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Product: Clc1ncc(-c2ccsc2)cn1

Procedure:
2-Chloro-5-bromopyrimidine and 3-thienyltributyltin are treated in the same manner as in Example 190 to give 2-chloro-5-(3-thienyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:16]([NH2:17])=[C:15]([C:18](=O)[CH2:19]C)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.Cl.C([OH:25])C>[Pd]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:16]3[NH:17][C:19]([OH:25])=[CH:18][C:15]=3[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ncnc(N2CCc3ccc(Cl)cc32)c1N
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: Oc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2[nH]1
Reaction time: 3 h

Procedure:
To a solution of 4-(6-Chloro-2,3-dihydro-indol-1-yl)-5-amino-6-methylacetylpyrimidine (541 mg, 1.55 mmol) in 40 mL of ethanol was added 25 mol % of 10% palladium on carbon (125 mg) and 0.11 mL of 1N HCl (1.55 mmol). The reaction mixture was hydrogenated for 3 hours at 50 psi. The reaction mixture was filtered through Celite and concentrated in vacuo. The brown residue was slurried in methanol and the white solid title product was filtered off (279 mg, 63%)LC-MS=287 (M+), RP18-HPLC RT: 5.61 min. MP: 250° C.(dec).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[OH-].[K+].CCOP(OCC)([CH2:17][C:18]#[N:19])=O.[Na+].[Cl-]>O>[C:18]([CH:17]=[C:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)#[N:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CN2CCC1CC2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CC=C1CN2CCC1CC2
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To a stirred solution of 3-quinuclidinone (50 g; 0.309 mol) in water (250 ml) was added potassium hydroxide (17.35 g; 0.309 mol). After 15 minutes, diethyl cyanomethyl phosphonate (109.6 g; 0.619 mol) was added with a further 125 ml water. A solution of potassium hydroxide (52.07 g; 0.928 mol) in water (250 ml) was added dropwise over 30 minutes. The reaction was left overnight, saturated with NaCl then extracted into ethyl acetate (6×200 ml). The organic extracts were combined, dried over anhydrous K2CO3 and concentrated in vacuo to give 3-cyanomethylidene quinuclidine (44 g; 96%, (96% pure-gc)) as a 2:1 mixture of Z:E isomers.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[OH:15].N1C=CC=CC=1.[C:22](Cl)(=[O:25])[O:23][CH3:24]>C(Cl)Cl.C(OCC)C>[OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:22]([O:23][CH3:24])=[O:25]
Reactant: COCOC1CC2=NOCC2C(O)C1O
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOC1CC2=NOCC2C(O)C1OC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
4,5-Dihydroxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (217 mg) was dissolved in 10 ml of methylene chloride, and 1 ml of pyridine and then 100 mg of methyl chlorocarbonate were added under ice cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with diethyl ether, washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous sodium sulfate, and concentrated was under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 137 mg of 4-hydroxy-5-methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 50%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31].[Cl-].[NH4+]>O1CCCC1.O>[Si:5]([O:8][CH2:9][C:10]1[S:11][C:12]([CH:30]=[O:31])=[C:13]([CH2:15][CH3:16])[CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCc1csc(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Temperature: 0 °C
Yield: 86 %

Procedure:
To a solution of t-butyl[(4-ethyl-2-thienyl)methoxy]dimethylsilane (1.3 g, 5.6 mmol) that was obtained in Example 10 (10a) in tetrahydrofuran (10 ml) was slowly added a 1.6 M solution of n-butyllithium in hexane (4.2 ml, 6.7 mmol) at −78° C. with stirring, and after raising the reaction temperature to 0° C., the resulting mixture was stirred for 30 minutes. Subsequently, the reaction temperature was lowered to −78° C. again under stirring, and to the reaction mixture was added N,N-dimethylformamide (0.86 ml, 11 mmol) with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (1.3 g) in a yield of 86% as a pale yellow oily product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-:15].[Na+]>[Ag]=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([OH:15])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 57 %

Procedure:
To a stirred suspension of 1.4 g of silver oxide in 20 ml of 6% aqueous sodium hydroxide was added dropwise 2.1 g of the 2-(4-isobutylphenyl)-propionaldehyde obtained in the procedure of Example 3(i) over 10 minutes at 60°C with stirring. The mixture was further stirred at 60°C for 15 minutes and then allowed to stand. The precipitate was filtered off and washed with hot water. The filtrate and the washing liquor were combined together, and the insoluble oil was removed by extracting with ethyl ether. The remaining aqueous phase was then extracted with ethyl ether, and the ether extract was washed with water, dried and then distilled under reduced pressure to remove the ether. The crude crystalline product so obtained was recrystallised from petroleum benzine, affording 1.3 g of 2-(4-isobutylphenyl)-propionic acid, M.P. 74.8°-76.5°C. Yield 57% (based on the theoretical).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:28]>C(OCC)C>[ClH:28].[ClH:28].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH2:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (70 mg, 0.185 mmol), in diethyl ether (10 mL) at 0° C. was added HCl in diethyl ether (5 mL) slowly dropwise over a period of 10 nuns, stirred the reaction mixture for 2 h. After completion, the reaction mixture was filtered under inert atmosphere and washed with hexane (10 mL) and EtOAC (5 mL), and dried under reduced pressure to get (50 mg, 86.2%) of (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine dihydrochloride as a pale yellow powder. 1H-NMR (D2O) δ (ppm): 1.52 (q, 1H), 1.63 (quin, 1H), 2.66 (m, 1H), 3.08 (m, 1H), 7.72 (t, 1H), 7.89 (d, 1H), 7.98 (d, 1H), 8.09 (s, 1H), 8.14 (d, 1H), 8.27 (d, 1H), 8.61 (s, 1H). MS (M+H): 279.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH:10]=[O:11].O1CCOCC1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:18][CH:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:10]=[O:11]
Reactant: Cc1cccc(C)c1CC=O
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(C)c1C(Br)C=O
Reaction time: 0.17 h
Yield: 103.8 %

Procedure:
2-(2,6-dimethylphenyl)-acetaldehyde (4.4 g, 29.7 mmol) was dissolved in DCM (30 mL) and dioxane (50 mL) and a solution of bromine (1.7 mL, 32.7 mmol) in DCM (30 mL) was added dropwise at room temperature. Completion of reaction was determined by GC/MS. Upon completion, sodium thiosulfate aqueous solution was added and stirred for 10 minutes. The layers were separated, and washed twice with DCM (100 mL) and combined organics with 10% aqueous LiCl solution (100 mL). The organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 7 g (93%) of 2-bromo-2-(2,6-dimethylphenyl)acetaldehyde as an orange oil. NMR confirmed the product, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([CH3:44])([CH3:43])[C:38](OCC)=[O:39])=[C:32]([C:45]([F:48])([F:47])[F:46])[CH:31]=3)=[O:28])=[C:22]([F:49])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][OH:39])=[C:32]([C:45]([F:46])([F:48])[F:47])[CH:31]=3)=[O:28])=[C:22]([F:49])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccc(OC)cc4)c(OCC)c3)cc2F)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a mixture of ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (3.5 g, 5.13 mmol) in THF (200 mL) cooled to 0° C. was added LAH (0.389 g, 10.25 mmol) in portions. The mixture was stirred at 0° C. for 30 min. The mixture was quenched with 15% NaOH (aq., 10 mL). The mixture was dried over Na2SO4. The mixture was filtered and the filtrate was concentrated. The residue was purified on silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.35) were combined and concentrated to yield a light yellow oil of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (3 g, 4.21 mmol, 82.0% yield): 1H NMR (400 MHz, CD3OD) δ: 7.93 (d, J=2.0 Hz, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.47-7.31 (m, 7H), 6.90 (d, J=8.4 Hz, 2H), 5.35 (s, 2H), 4.17-4.10 (m, 2H), 3.82-3.74 (m, 5H), 3.31-3.30 (m, 2H), 2.77 (s, 2H), 1.41 (t, J=6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 635 (M−120).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cccc(Br)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cccc(Br)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol) and 3-bromo-benzaldehyde (18.5 g, 100 mmol) in ethanol (100 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (20 g, 60%) as a white solid: LC/MS m/e calcd for C16H14BrNO2 M+: 332.2, observed: 332.0, 334.0.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([N:18]([CH3:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])C.CC[O-].[Na+].C(O)(=O)C.O>C(O)C>[CH2:24]([O:23][C:21]([CH:20]1[CH2:19][N:18]([CH3:26])[C:7]2[N:8]=[C:9]3[CH:10]=[C:11]([F:17])[C:12]([F:16])=[CH:13][C:14]3=[CH:15][C:6]=2[C:4]1=[O:5])=[O:22])[CH3:25]
Reactant: CCOC(=O)CCN(C)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CN(C)c2nc3cc(F)c(F)cc3cc2C1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 94 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(b-ethoxycarbonylethyl)amino]quinoline in 300 cm3 of absolute ethanol is added in the course of 80 minutes to a solution of 26.6 g of sodium ethylate brought to reflux in 900 cm3 of absolute ethanol. The suspension obtained, still refluxing, is stirred for a further 15 minutes. 38 cm3 of glacial acetic acid are then introduced in the course of 30 minutes. The reaction mixture is stirred for a further 15 minutes and, with the mixture still refluxing, 500 cm3 of water are then introduced in the course of 45 minutes. The suspension obtained is cooled to approximately 20° C. The precipitate is drained at approximately 20° C. and washed with twice 300 cm3 of water. The wet product is dried under reduced pressure (20 kPa) at approximately 60° C. 71.5 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl- 4-oxo-1,2,3,4-tetrahydro-benzo[b][1,8]naphthyridine are isolated in the form of a yellow solid, melting point 188° C.
Reaction SMILES: [CH2:1]([N:4]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([F:18])[CH:6]=1)[CH:2]=[CH2:3].[I-:29].O1CCNC1=O>>[I:29][CH2:3][CH:2]1[O:20][C:19](=[O:21])[N:4]([C:5]2[CH:6]=[C:7]([F:18])[C:8]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:9]([F:11])[CH:10]=2)[CH2:1]1
Reactant: [I-]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2ccncc2)c(F)c1
Agent: O=C1NCCO1
Product: O=C1OC(CI)CN1c1cc(F)c(-c2ccncc2)c(F)c1

Procedure:
Following the general procedure of PREPARATION 5 and making non-critical variations but starting with N-allyl-N-carbobenzyloxy-4-(4-pyridyl)-3,5-difluoraniline (PREPARATION 10, 241 mg, 0.634 mmol) is converted to the oxazolidinone iodide. The crude product is not purified further, NMR (CDCl3) δ 8.70, 7.44, 7.32, 4.85-4.73, 4.19, 3.80, 3.50, 3.40.