Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)N.OS(O)(=O)=O.N([O-])=O.[Na+].[I-:21].[K+].N#N>O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([I:21])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: [I-]
Reactant: COc1cc(N)cc(OC)c1
Agent: N#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: COc1cc(I)cc(OC)c1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To an ice-salt cooled solution of 4.55 g (29.7 mmol) of 3,5-dimethoxyaniline in 50 mL of water was added 4 mL of 98% H2SO4. After the solution had cooled to −5° C., a solution of 2.4 g (34.8 mmol) of NaNO2 in a minimum amount of water was added, keeping the temperature below 0° C. The reaction was stirred for 10 min, then 50 mL of diethyl ether was added. A solution of 15 g (90 mmol) of potassium iodide in a minimum amount of water was added slowly to control the evolution of N2. After 3 h, the layers were separated, and the aqueous layer was extracted with additional ether (2×50 mL). The combined ether layers were back extracted with 5% (w/v) NaHSO3(aq) (2×50 mL), 1 M HCl (1×50 mL), 2M NaOH (1×50 mL), then brine (1×25 mL), dried over MgSO4, filtered, and concentrated to a dark oil. The product was purified by silica gel chromatography, eluting with 10% ethyl acetate:hexanes to provide the titled compound (4.80 g, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][Si](C)(C)C)[C:5]([O:7][CH3:8])=[O:6].C(O)=[O:19]>>[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])(=[O:19])[CH3:13]
Reactant: O=CO
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Product: COC(=O)c1ccc(C(C)=O)c(O)c1
Temperature: 80 °C
Yield: 83 %

Procedure:
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (540 mg, 2.17 mmole) is combined with 4 ml formic acid under nitrogen. The reaction is warmed to 80° C. for 12 h, is cooled to rt, and the volatiles are removed in vacuo. The black residue is chromatographed over 25 g silica gel (230-400 mesh) eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated to provide 350 mg (83%) of methyl 4-acetyl-3-hydroxybenzoate as a pale yellow solid. 1H NMR (CDCl3) δ 2.70, 3.95, 7.54, 7.64, 7.82, 12.10 ppm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:2]=1>C(O)(=O)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2]1
Reactant: CCOC(=O)c1cnc2ccccc2c1
Solvent: CC(=O)O
Product: CCOC(=O)C1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
Borane-pyridine complex (8 M, 292 mL, 2.34 mmol) was added to a solution of Ethyl quinoline-3-carboxylate (235 mg, 1.17 mmol) in acetic acid (10 mL). The solution was stirred at 25° C. for 20 h. The reaction mixture was concentrated in vacuo, basified with 1 M sodium carbonate (30 mL), and the product was extracted with dichloromethane (3×35 mL). The organic layers were dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (10% to 20% EtOAc/hexane) afforded the title compound (239 mg, 1.15 mmol). MS m/z: 206 (M+1).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:29]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccccc1C(=O)O
Product: CCN1CCCC1CNC(=O)c1ccccc1OC/C=C(\C)CCC=C(C)C
Yield: 80 %

Procedure:
In a manner identical to Example 15, 2-geranyloxybenzoic acid (1.37 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.53 g (80%) of the aimed compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]#[N:27]>CCO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][C:24]#[N:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Reactant: N#CCCN
Solvent: CCO
Product: CCC(NCCC#N)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of the compound of Example 1 Step 4 (2.0 g, 5.5 mmol) in EtOH (50 mL) treated 3-amino-propionitrile (1.55 g, 22.1 mmol) and stirred at reflux for 6 h. The mixture was cooled to room temperature and concentrated under vacuum. The resulting material was purified by preparative reverse-phase HPLC (CH3OH/H2O) on a YMC S10 ODS 50×500 mm column to afford the desired product as a yellow glass (1.2 g, 62%); 1H NMR (CD3OD): δ 7.38 (m, 5H), 5.65 (d, J=16.5 Hz, 1H), 5.30 (d, J=16.5 Hz, 1H), 4.65 (t, J=6.0 Hz, 1H), δ 3.15 (m, 1H), 2.72 (m, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.59 (s, 3H), 1.92 (m, 2H), 0.89 (t, J=7.5 Hz, 3H)); LC/MS (ESI): 352 (M+H)+.
Reaction SMILES: Cl.O.[C:3]([NH:7][C:8]([C@@H:10]1[CH2:15][N:14](C=O)[CH2:13][CH2:12][N:11]1[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>CC(C)=O>[C:3]([NH:7][C:8]([C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(C=O)CCN1C(=O)C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)C(F)(F)F
Temperature: 20 °C
Yield: 81.1 %

Procedure:
A mixture of 50.5 g (430 mmol) of 32% hydrochloric acid and 50 ml of water was added to 32.0 g (103 mmol) of (S)-4-formyl-1-(trifluoroacetyl) piperazine-2-carboxylic acid tert-butylamide in 200 ml of acetone and the resulting mixture was heated at 60° to 65° C. for 2.5 hours. After cooling to 20° C., neutralization was carried out with triethylamine in such a way that the temperature remained below 30° C. The solvent was evaporated off, and 100 ml of water and 200 ml of methyl isobutyl ketone were added. At 50° C. the phases were separated and the aqueous phase was re-extracted with twice 100 ml of methyl isobutyl ketone. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness to give 23.5 g (80%) of the title compound in the form of a slightly reddish solid. Recrystallization from toluene/diisopropyl ether gave the title compound in the form of a white crystalline powder. The melting point of the title compound was: 143.5° to 144.2° C. Other data concerning the title compound was:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:74][CH2:75][CH2:76][CH2:77][N:78]1[CH:82]=[CH:81][N:80]=[CH:79]1>CN(C=O)C>[N:78]1([CH2:77][CH2:76][CH2:75][NH:74][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:30])[CH:82]=[CH:81][N:80]=[CH:79]1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-(3-aminopropyl)imidazole (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with toluene/methanol (8:2), which after evaporation of the solvents under vacuum gave N-{4′-[(3-imidazol-1-ylpropylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (12 mg, 24%). NMR; δH [2H6]-DMSO 10.31,(1H, s), 8.60,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.67,(2H, m), 7.45,(2H, d), 7.30,(1H, d), 7.22,(1H, s), 6.96,(1H, s), 6.86,(1H, s), 4.03,(2H, t), 3.43,(4H, m), 3.26,(2H, q), 2.20,(3H, s), 1.99-1.93,(6H, m). LCMS: retention time 2.24 min, MH+509.
Reaction SMILES: Cl.[CH3:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9]>>[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([NH:3][CH3:2])=[O:9]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(F)c(F)c1

Procedure:
Using methanamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained as an off-white solid (75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3H) 7.55 (dt, J=10.61, 8.34 Hz, 1H) 7.72 (dddd, J=8.59, 4.55, 2.15, 1.39 Hz, 1H) 7.86 (ddd, J=11.68, 7.89, 2.15 Hz, 1H) 8.48-8.59 (m, 1H). ESI-MS: m/z 172.1 (M+H)+. mp=142.7-145.0° C.
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=2)[C:6]1=[O:16])(C)(C)C.O.[NH2:18]N>CC(O)=O.O>[CH3:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:16])[NH:18][N:5]=[CH:13]2
Reactant: Cc1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)[nH]ncc2c1
Temperature: 80 °C

Procedure:
To a solution of 2-tert-butyl-3-hydroxy-5-methylisoindolin-1-one (10.54 g, 48.1 mmol) in AcOH (250 ml) charged to a 500 mL round bottom and stirred at 80° C., hydrazine hydrate (3.51 ml, 72.1 mmol) was added. The reaction mixture was stirred at 80° C. for 90 min. The reaction mixture was then cooled and diluted with water and extracted with 4 L DCM. The organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum to give 6-methylphthalazin-1(2H)-one. MS (M+H)+ 161.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.CN(C=O)C.[H-].[Na+]>CO>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
To a mixture of Solketal (66.1 g, 0.5 mol), 1-bromotetradecane (159.4 g, 0.575 mol), and DMF (800 ml) was added 60% NaH (26.0 g, 0.65 mol) in oil dispersion in 3 portions for 1 hr. The mixture was stirred at room temperature for 1 day and methanol (20 ml) was added to destroy the excess NaH. This was then poured into 1500 ml of ice-water and the aqueous layer was extracted with hexanes (2000 ml). The combined organic layers were evaporated to dryness and the oily residue was refluxed in 10% HCl/methanol (conc. HCl, 250 ml and methanol, 675 ml) for 30 min followed by stirring at room temperature overnight. The white flaky solid was filtered and washed with methanol (122 g). The additional product was obtained from the filtrate (5.7 g); Total 127.7 g (88.5%). The crude product was recrystallized from diethyl ether; Yield 99.7 g (69.1%), mp 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([N:13]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.1 %

Procedure:
Methyl 5-chloro-3-(cyclopentylamino)-2-methylbenzoate (1.2 g, 4.46 mmol) was dissolved in DMF (12 mL) and cooled to 0° C. NaH (0.21 g, 8.92 mmol) was added after 10 minutes and allyl bromide (1.07 g, 8.9 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then heated at 80 0° C. for 18 h. The reaction was quenched with ice water and extracted with ethyl acetate. Combined organic layers were dried, concentrated giving crude methyl 3-(allyl(cyclopentyl)amino)-5-chloro-2-methylbenzoate (0.4 g, 29.4%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([NH2:43])=O)[CH2:35][CH2:34]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]#[N:43])[CH2:35][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(N)=O)CC2)c2ncnn12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC#N)CC2)c2ncnn12
Reaction time: 2 h

Procedure:
To a solution (10 mL) of 2-({trans-4-[5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetamide (0.16 g) and pyridine (0.089 mL) in tetrahydrofuran was added trifluoroacetic acid anhydride (0.12 mL) at 0° C., and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.059 g, 38%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[N:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1)=[C:9]=[S:10].Cl>O1CCOCC1>[SH:10][C:9]1[N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COC(CN)OC
Reactant: N#Cc1ccc(N=C=S)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Aminoacetaldehyde dimethyl acetal (5.98 mL, 55.36 mmol) was added to a stirring slurry of 4-isothiocyanato-1-naphthonitrile (11.64 g, 55.36 mmol) in dioxane (55 mL), and stirring continued for 1 h (sizeable exotherm observed). HCl was added (4.8 mL, 58.13 mmol) and the mixture heated to 105° C. for 18 h. The mixture was then concentrated, methanol added (100 mL), concentrated again, more methanol added (100 mL) and sonicated. Filtration provided 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile as a tan solid (8.33 g, 60%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][CH2:6][C:5]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])[CH2:4][O:3]1>ClCCl.[Au](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:25])[O:3][CH2:4][C:5]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:8]2[O:13][C:11]([CH3:12])=[CH:10][N:9]=2)[CH2:6][O:7]1
Reactant: C#CCNC(=O)C1(NC(=O)OCc2ccccc2)COC(C)(C)OC1
Agent: Cl[Au](Cl)Cl
Solvent: ClCCl
Product: Cc1cnc(C2(NC(=O)OCc3ccccc3)COC(C)(C)OC2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.8 %

Procedure:
Under an argon atmosphere, to a solution of 400 mg of benzyl [2,2-dimethyl-5-(prop-2-yn-1-ylcarbamoyl)-1,3-dioxan-5-yl]carbamate in 4 ml of dichloromethane was added 104 mg of gold (III) chloride, followed by stirring at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 35 mg of benzyl [2,2-dimethyl-5-(5-methyl-1,3-oxazol-2-yl)-1,3-dioxan-5-yl]carbamate.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[NH:12][CH:11]=[C:10]3[C:17]([O:19]C)=[O:18])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[NH:12][CH:11]=[C:10]3[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc12
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A solution of methyl 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylate (50 mg, 0.14 mmol) in methanol (1.5 mL) and sodium hydroxide (1 M, 0.50 mmol, 0.50 mL) was stirred at 75° C. for 24 hours. The cooled reaction mixture was neutralized to an acidic pH with 1M HCl and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Methylene chloride was then added and solid precipitated. The slurry was stirred for 30 minutes then filtered and washed with methylene chloride and a small amount of ethyl acetate. The solids were dried in vacuo to provide the desired product as a tan solid (17 mg, 35% yield). MS (ES+) 348.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.14 (br. s., 1H), 11.98 (br. s., 1H), 8.10 (d, J=2.93 Hz, 1H), 8.01 (s, 1H), 7.75 (t, J=8.42 Hz, 4H), 7.67 (s, 1H), 7.54 (d, J=8.05 Hz, 2H), 7.50 (t, J=7.56 Hz, 2H), 7.32-7.45 (m, 1H).
Reaction SMILES: BrCC(C1C=CN=C(Cl)C=1)=O.ClC1C=C(C(=O)C)C=CN=1.ClC1C=C(C#N)C=CN=1.BrCC(C1C=CN=C(SC)N=1)=O.OOS([O-])=O.[K+].FF.Br[CH2:52][C:53]([C:55]1[C:60]([F:61])=[CH:59][N:58]=[C:57]([Cl:62])[N:56]=1)=[O:54]>>[Cl:62][C:57]1[N:56]=[C:55]([C:53](=[O:54])[CH3:52])[C:60]([F:61])=[CH:59][N:58]=1
Reactant: O=C(CBr)c1nc(Cl)ncc1F
Agent: CC(=O)c1ccnc(Cl)c1
Agent: CSc1nccc(C(=O)CBr)n1
Agent: FF
Product: CC(=O)c1nc(Cl)ncc1F

Procedure:
Halopyridine 9, wherein L is halogen (9A) may be obtained, for example, from 2-bromo-1-(2-chloro-pyridin-4-yl)-ethanone prepared by halogenation of 1-(2-chloropyridin-4-yl)ethanone, obtainable from 2-chloro-4-cyano pyridine, as described in J. Het. Chem., 1983, 20, 533. 1-[2-(Methylthio)pyrimidin-4-yl]derivative 9, wherein L is CH3—S— (9B), obtainable from 2-bromo-1-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone (described in WO03/011838), may be activated to the corresponding sulfoxide or sulfone 9, wherein L is CH3—S(O)— or CH3—S(O)2— (9D), by oxidation, for example with oxone. Halopyrimidine derivative 9, wherein L is halogen and R5 is fluorine (9C), may be instead prepared from 2-bromo-1-(2-chloro-5-fluoropyrimidin-4-yl) ethanone, obtained by halogenation of 1-(2-chloro-5-fluoropyrimidin-4-yl) ethanone, in turn prepared as described in WO04/058762.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:5]=1[O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:13]2[CH2:16][CH3:17])=[CH:9][N:8]=1.Br[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>C1COCC1.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]([C:12]1[N:13]([CH2:16][CH3:17])[C:14]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([O:6][C:5]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:4]=1[F:3])[N:15]=2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34]
Reactant: CCn1c(Nc2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Reactant: CNC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(N(CC(=O)NC)c2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Reaction time: 1 h
Yield: 38 %

Procedure:
Sodium hydride (60% in oil, 0.010 g, 0.25 mmol) is added to a solution of [2-(2,6-difluorophenoxy)-9-ethyl-9H-purin-8-yl]-(2-chlorophenyl)-amine, 14, (0.1 g, 0.25 mmol) in THF (3 mL). After 5 minutes at room temperature 2-bromo-N-methyl-acetamide (0.06 mL, 0.37 mmol) is added and stirring is continued for 1 hour. The mixture is diluted with H2O (25 mL) and extracted three times with EtOAc (50 mL). The combined organic layers are washed with brine, dried over MgSO4, concentrated in vacuo and the residue purified by HPLC to afford 45 mg (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 7.54-7.59 (m, 2H), 7.15-7.36 (m, 4H), 7.04 (t, J=7.8 Hz, 2H), 4.53 (s, 2H), 3.61 (q, J=7.2 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H); ESI/MS: 473 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][OH:20])[C:16]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH:19]=[O:20])[C:16]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:15]2)=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-ylmethanol (11.7 g), active manganese dioxide (20.0 g) and tetrahydrofuran (150 ml) was stirred at room temperature for 2 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (10.9 g, yield 94%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: NC1C(F)=C(C=CC=1Cl)CC1(C(OC(C)(C)C)=O)CC1.[NH2:21][C:22]1[C:23]([F:40])=[C:24]([C:36]([Cl:39])=[CH:37][CH:38]=1)[CH2:25][C:26]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1.C1COCC1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C@H:53]([C@@H:57]([CH3:62])[C:58]([F:61])([F:60])[F:59])[C:54](Cl)=[O:55])=[CH:49][CH:48]=1>O>[Cl:39][C:36]1[C:24]([CH2:25][C:26]2([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]2)=[C:23]([F:40])[C:22]([NH:21][C:54](=[O:55])[C@H:53]([C:50]2[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][CH:51]=2)[C@@H:57]([CH3:62])[C:58]([F:59])([F:60])[F:61])=[CH:38][CH:37]=1
Reactant: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2c(Cl)ccc(N)c2F)CC1
Agent: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2F)CC1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]([C@H](C(=O)Nc1ccc(Cl)c(CC2(C(=O)OC(C)(C)C)CC2)c1F)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.0 mg of a mixture of tert-butyl 1-(3-amino-4-chloro-2-fluorobenzyl)cyclopropanecarboxylate and tert-butyl 1-(3-amino-6-chloro-2-fluorobenzyl)cyclopropanecarboxylate (Example 24A/25A, ratio about 1.5:1) were dissolved in 0.16 ml of abs. THF, the solution was cooled to −10° C. and a solution of 38 mg (0.132 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl chloride in about 0.1 ml of abs. THF was added dropwise. After the addition had ended, the mixture was slowly warmed to RT, and after 2 h, water was added. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The product mixture obtained was separated by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 23.2 mg (38% of theory) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 186A) and 18.7 mg (31% of theory) of tert-butyl 1-(6-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 187A).