Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1cccc(CN=C=O)c1
Product: Cc1cccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1

Procedure:
Example 4 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-3-methylbenzene (19.1 μl) to give the title compound (0.0382 g). LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].B(F)(F)F.CCOCC.[CH3:20][C:21]1([CH:27]=[CH2:28])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>O1CCOCC1.CCOCC>[CH3:20][C:21]1([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:27][CH2:28][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[CH3:9])[O:10]1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: C=CC1(C)CCC(=O)O1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(C)c2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluant ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane to afford a white crystalline product in a yield of 40%. M.P.: 148-149° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([F:34])[C:28]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[C:27]([F:34])[C:28]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(F)c(-c2cnco2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3cc(F)c(-c4cnco4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3,5-difluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.19 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][O:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: COCCNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (53%). MS (ESI): m/z=503.095 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:21][CH2:5][C:4]1[CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccc(Oc2ccccc2Cl)cc1CCl

Procedure:
A mixture of 2-methoxy-5-(2-chlorophenoxy)benzyl alcohol (8 g), thionyl chloride (4.4 ml) and pyridine (3 drops) in dried benzene (60 ml) was treated in a similar manner to that of Example 3-(6) to give oily 2-chlorophenyl 3-chloromethyl-4-methoxyphenyl ether (8.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)O.[CH2:26](N(CC)CC)[CH3:27].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(Br)cc2)N1CC(F)(F)F
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCC1(c2ccc(Br)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Reaction time: 0.08 h

Procedure:
To a −18° C. solution of 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (1 g, 2.3 mmol) in anhydrous THF (10 mL) was added triethylamine (1.6 mL, 11 mmol). The reaction was stirred for 5 min and then thionyl chloride (0.18 mL, 2.5 mmol) was added dropwise. After 10 min, 1M ethylmagnesium bromide in THF (9 mL, 9 mmol) was added. The reaction mixture was warmed from −18° C. to 0° C. and allowed to stir for 30 min and then quenched with 15 mL 1N aqueous HCl and extracted with 50 mL ethyl acetate. The organic layer was washed with brine (60 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (90 g silica gel cartridge, linear gradient 10-70% EtOAc/hexanes) gave 6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, NH); 7.53 (br d, 2H, J=8.79 Hz); 7.28 (br d, 2H, J=8.54 Hz); 7.11 (dd, 1H, J=8.54 and 2.19 Hz); 6.69 (d, 1H, J=8.55 Hz); 6.46 (d, 1H, J=2.20 Hz); 3.87 (dq, 1H, J=9.28 and 16 Hz); 3.52 (dq, 1H, J=8.30 and 17 Hz); 2.39 (dq, 1H, J=7.08 and 14 Hz); 2.22 (dq, 1H, J=7.08 and 14 Hz); 0.90 (t, J=7.08 Hz, 3H); MS (Electrospray): m/z 447.1 (M+H, Br=79).
Reaction SMILES: [C:1]([CH:5]1[CH2:9]SC[C:6]1=O)([O:3][CH3:4])=[O:2].C[O-].[Na+].CI.[CH3:16][S:17]([CH3:19])=[O:18]>O>[C:1]([C:5]1([CH3:9])[CH2:19][S:17](=[O:18])[CH2:16][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CSCC1=O
Reactant: CS(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)C1(C)CCS(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 4.65 g (29.0 mmol) of 4-carbomethoxytetrahydro-3-thiophenone in 20 ml of dry DMSO cooled in a cold-water bath at 12° C. under argon was added 1.73 g (32.0 mmol) of sodium methoxide. The mixture was stirred 30 minutes and a solution of 4.97 g (35.0 mmol) of methyl iodide in 1 ml of dry DMSO was added dropwise. The mixture was stirred overnight at room temperature, than diluted with water (60 ml) and extracted with methylene chloride (3×75 ml). The extract was washed with water (50 ml) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 5.4 g of an oil. The oil was flash chromatographed on silica gel eluting with 3:1 hexane:ether to give 1.49 g (30%) of the product as an oil; NMR (deuteriochloroform): δ 3.76 (S, 3H), 3.70 (m, 1H), 3.50 (dd, 1H), 3.30 (dd, 1H), 2.83 (d, 1H), 1.46 (S, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:13]([C:23]#[N:24])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)[O:31][C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=O)[O:27]1>>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[C:13]([C:23]#[N:24])=[CH:12][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:1][C:28](=[O:27])[CH2:29][C:30]([C:32]3[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=3)=[O:31])[CH:3]=2)[CH:15]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1Cl
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4Cl)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-4-(2-chloro-phenyl)-1H-pyrrole-3-carbonitrile (Example E2) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange-brown solid (203 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: NC(=O)c1ccc(O)c(N)c1

Procedure:
A mixture of 4-hydroxy-3-nitrobenzamide D125 (0.49 g, 2.69 mmol), cyclohexene (1.105 g, 13.45 mmol) and 10% palladium on carbon (0.143 g, 0.135 mmol) in ethanol (20 mL) was heated to reflux under argon for 3 hr. The cooled mixture was filtered through celite and the filtrate concentrated to dryness in vacuo to afford a yellow/brown solid. The product was purified by silica gel chromatography eluting with 0-15% 2M ammonia in MeOH/DCM. The title compound was isolated as a pale brown powder, 0.26 g, 57.2%.
Reaction SMILES: [CH:1]1[C:4]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]4[CH:26]=[CH:25][C:22]5[CH:23]=[CH:24][C:21]=5[CH:20]=4)[C:11]=3[C:12]#[N:13])=[CH:8][C:3]=2[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:23]1[C:22]2[CH:25]=[CH:26][C:19]([O:18][C:14]3[CH:15]=[CH:16][CH:17]=[C:10]([O:9][C:7]4[CH:6]=[CH:5][C:4]5[CH:1]=[CH:2][C:3]=5[CH:8]=4)[C:11]=3[CH2:12][NH2:13])=[CH:20][C:21]=2[CH:24]=1
Reactant: N#Cc1c(Oc2ccc3c(c2)C=C3)cccc1Oc1ccc2c(c1)C=C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1c(Oc2ccc3c(c2)C=C3)cccc1Oc1ccc2c(c1)C=C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 500 ml, 4-necked round-bottomed flask equipped with an overhead mechanical stirrer, a thermometer/adaptor, a reflux condensor and a funnel was added 2,6-di-(4-benzocyclobutenoxy)benzonitrile followed by 260 ml of anhydrous diethyl ether. The resultant mixture was placed in an ice bath and stirred under a nitrogen atmosphere. When the internal temperature reached 0° C., lithium aluminum hydride was added through the attached funnel in 3 portions (0.69 g, 0.96 g, 0.50 g), each addition followed by washing the funnel with about 10 ml Et2O, over a period of 15 minutes. The resulting mixture was stirred at 0° C. for 20 minutes, then the ice bath was removed and the mixture. was allowed to warm to room temperature. The reaction mixture was then refluxed gently for 17 hours.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1cc(C(C)=O)ccc1OCC(F)F
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)F
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (1.09 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone (0.77 g, 3.35 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[SH:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3c2)c(Cl)c1

Procedure:
2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene was synthesized (100%) from 3-chloro-4-fluoro-nitrobenzene (Aldrich) and napthalene-2-thiol (Avocado) in a similar manner as described in example 89.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24]>ClCCl>[OH:1][C:2]1[C:3]([C:8]([NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)CN
Reactant: COC(=O)c1nccnc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1nccnc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
In 6 mL of dichloromethane is suspended 0.30 g of methyl 3-hydroxy-2-pyrazinecaroxylate obtained according to the method described in literature [J. Heterocycl. Chem., 34, 27 (1997)]. To the suspension are successively added 0.54 mL of triethylamine and 0.29 g of glycine methyl ester hydrochloride. The resulting mixture is stirred at ambient temperature for 5 hours. After cooling, the solvent is distilled off under reduced pressure. The residue is purified by reverse phase column chromatography (eluent: water) to obtain 0.16 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)-carbonyl]amino}acetate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[I:22]Cl.C([O-])(O)=O.[Na+]>CC(O)=O.O>[I:22][C:7]1[CH:6]=[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: ClI
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 2-Isopropyl-4-methoxy-1-(toluene-4-sulfonyl)-benzene (10 g, 31.25 mmol) in HOAc (10 ml) was added a solution of ICl (9.6 g, 59.26 mmol) in HOAc (10 ml) and H2O (5 ml). The reaction mixture was stirred at room temperature for 16 hrs and basified by saturated NaHCO3 solution. The aqueous solution was extracted into EtOAc which was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-Iodo-4-isopropyl-2-methoxy-5-(toluene-4-sulfonyl)-benzene (12.35 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[I:10]Cl.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([I:10])[CH:6]=[C:5]([F:9])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cccc1F
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cc(I)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
60 g of 2,6-difluoroaniline was dissolved in 180 ml of acetic acid. A solution containing 75 g of iodine chloride dissolved in 48 ml of acetic acid was added dropwise therein, and then agitated at 80° C. for 2 hours. The reaction solution was poured into water, and the resulting deposited crystals were filtrated and washed with water. The crystals were recrystallized with methanol, vacuum distilled (125° C./22 mmHg), and recrystallized again with methanol to obtain 57 g of 2,6-difluoro-4-iodoaniline.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH:25]1[O:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:27]1[CH2:26][CH:25]1[CH2:24][O:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: Cc1cccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[4'-hydroxyanilino]6-(3'-methylanilino)pyrimidine (1.14 g), 1-bromo-2,3-epoxypropane-(0.5 ml) and potassium carbonate (1.24 g) in DMSO (12 ml) was stirred at ambient temperature for 16 hours to give 4-[4'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine (0.70 g);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:18]=3[CH:36]=2)=[CH:4][CH:3]=1.[OH:37]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:18]=3[CH:36]=2)=[O:37])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C)cc3)cc21
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([C:30]5[N:29]=[C:28]([C:27]([F:42])([F:26])[F:43])[O:32][N:31]=5)[CH:34]=4)=[O:37])[CH2:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2csc(C3CCCNC3)n2)cc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCC(c2nc(-c3ccc(F)cc3)cs2)C1
Yield: 28 %

Procedure:
This compound was synthesized from 4-(4-fluorophenyl)-2-(piperidin-3-yl)thiazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (41 mg, yield 28%). 1H NMR (400 MHz, MeOD) δ 8.20-8.18 (m, 1H), 8.09 (m, 1H), 7.85 (m, 2H), 7.66-7.65 (d, J=4.3 Hz, 2H), 7.59 (m, 1H), 7.10-7.05 (t, J=8.4 Hz, 2H), 3.91 (m, 1H), 3.65 (m, 1H), 3.49-3.39 (m, 2H), 2.36-2.31 (m, 1H), 2.12-2.03 (m, 3H), 1.77-1.74 (m, 1H). MS (ESI) m/z: Calculated for C24H18F4N4O2S: 502.11. found: 503.1 (M+H)+
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]4[NH:45][C:44]([C@@H:46]5[CH2:50][CH2:49][CH2:48][N:47]5C(OC(C)(C)C)=O)=[N:43][C:42]=4[Cl:58])=[CH:37][CH:36]=2)[CH:29]=[CH:28]3)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[Cl:58][C:42]1[N:43]=[C:44]([C@@H:46]2[CH2:50][CH2:49][CH2:48][NH:47]2)[NH:45][C:41]=1[C:38]1[CH:37]=[CH:36][C:35]([C:30]2[CH:29]=[CH:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:22]4[NH:21][C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)=[N:24][CH:23]=4)[CH:26]=3)[CH:31]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5[nH]c([C@@H]6CCCN6C(=O)OC(C)(C)C)nc5Cl)cc4)ccc3c2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1nc([C@@H]2CCCN2)[nH]c1-c1ccc(-c2ccc3cc(-c4cnc([C@@H]5CCCN5)[nH]4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
TFA (2 mL) was added to a solution of (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (75 mg) in DCM (10 mL) and the mixture was stirred for 2 h at room temperature. The solvents were removed in vacuo and the residue was taken up in a solvent mixture of 1:1 methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford 4-chloro-2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole (40 mg, 0.079 mmol) as yellow solid. LC-MS retention time 1.353 min; m/z 509.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD, partially soluble only) δ ppm 8.20 (s, 1H), 8.09 (s, 1H), 7.88-7.96 (m, 2H), 7.76-7.88 (m, 6H), 7.51 (s, 1H), 4.50 (t, J=7.28 Hz, 1H), 4.35 (t, J=7.15 Hz, 1H), 3.03-3.31 (partially masked by methanol, m, 4H), 2.24-2.42 (m, 2H), 1.88-2.21 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[C:20](=[O:28])[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4ccccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 491.5 (M+H+).