Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[N:28]2[C:29]3[C:34]([N:25]([C:23]([C:22]4[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]5[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=5[CH3:1])=[CH:39][CH:38]=4)=[O:24])[CH2:26][C:27]2=[CH:37][CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1.5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 3 mmol of triethylamine. After stirring for 15 minutes, 1.5 mmol of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid, m.p. 206°-207° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([I:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C.C(OC)(C)(C)C.O.COC1C=CC(CCl)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cc(Br)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(COc2cc(Br)cc(I)c2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
3-Bromo-5-iodo-phenol (8.48 g, 28.37 mmol) was dissolved in DMF (50 mL) under dry argon and cooled to 0° C. Then potassium carbonate (3.92 g, 28.37 mmol) was added, followed by drop wise addition of 4-methoxybenzyl chloride (3.7 mL, 27.0 mmol). The mixture was slowly warmed to room temperature and stirred for 20 h. Additional 4-methoxybenzyl chloride (0.19 mL, 1.4 mmol) was added and the mixture was stirred for additional 24 h at room temperature. The reaction mixture was diluted with tert-butylmethyl ether (300 mL) and water (150 mL). The layers were separated and the aqueous one extracted with tert-butylmethyl ether (2×150 mL). The combined organics were washed with water and brine (150 mL), dried (Na2SO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (330 g, AcOEt/heptane 1:9). 1-Bromo-3-iodo-5-(4-methoxy-benzyloxy)-benzene (8.80 g, 59%, purity 80%, HPLC 220 nm) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH:37]([OH:39])[CH:36]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:38][CH:37]([OH:39])[CH:36]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CC(O)C(N2CCCC2)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC(O)C(N4CCCC4)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and Racemic-1′-((2-bromophenyl)sulfonyl)-[1,3′-bipyrrolidin]-4′-ol in Step B. MS (ESI): mass calcd. for C24H26FN5O3S, 483.17; m/z found, 484.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.60-8.57 (m, 1H), 8.15 (d, J=6.8, 1H), 8.11 (d, J=1.5, 1H), 7.97 (m, 1H), 7.61 (dd, J=7.5, 6.1, 1H), 7.55-7.49 (m, 1H), 7.38-7.28 (m, 3H), 4.68 (s, 2H), 4.18-4.12 (m, 1H), 3.30 (dd, J=10.5, 6.2, 1H), 3.23 (dd, J=10.1, 6.8, 1H), 2.95 (dd, J=10.0, 6.4, 1H), 2.88 (dd, J=10.4, 4.4, 1H), 2.63-2.57 (m, 1H), 2.52-2.38 (m, 5H), 1.74-1.67 (m, 4H).
Reaction SMILES: Cl.C[NH:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>C(Cl)(Cl)Cl>[C:9]([NH:3][CH2:4][CH2:5][NH2:6])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: CNCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.2 %

Procedure:
The intermediate N-t-BOC, N-methyl-ethylenediamine monohydrochloride prepared in example 5 (10 mmol, 2.1 g) was stirred with 2M NaOH (11 cm3) at room temperature for 10 min. The solution was then cooled to 0° C., and to this, was added a solution of methacryloyl chloride (11 mmol, 1.1 cm3) in chloroform (30 cm3), dropwise. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 1 h. The organic and aqueous phases were then separated, and the aqueous phase extracted with chloroform. The organic extracts were combined, dried (MgSO4), filtered and conc. in vacuo, to give the crude product. The crude product was stirred at room temperature over a slurry of basic alumina in chloroform for 18 hr. Removal of the alumina and concentration of the filtrate then gave a pale yellow oil. Purification by flash chromatography (silica gel, diethyl ether:hexane:methanol elution) afforded N-t-BOC, N-methyl, N′-methacryloyl-ethylenediamine (Rf 0.51) as a yellow oil (1.63 g, 67%). δH (400 MHz; CDCl3) 6.94 (1H, br s), HNOC(H3C)C═CHaHb; 5.74 (1H, br m), (H3C)C═CHaHb; 5.30 (1H, br m), (H3C)C═CHaHb; 3.43 (4H, br m). 2×CH2; 2.87 (3H, s), N(CH3); 1.93 (3H, br m), CH3; 1.44 (9H, s), C(CH3)3. δC (75.4 MHz; CDCl3) 168.52, NHOC(H3C)C═CH2; 157.33, NHCO2C(CH3)3; 139.36, (H3C)C═CH2; 119.81, (H3C)C═CH2; 80.85 C(CH3)3; 47.32, CH2N(CH3)OC(H3C)C═CH2; 39.32, CH2NHCO2C(CH3)3; 34.68, N(CH3); 28.33, C(CH3)3; 18.47, CH3. Found: (MH+) 243.17178.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.CS(C)=O.[BH4-].[Na+].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]([N:3]1[CH2:6][CH2:7][CH:4]1[CH2:5][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CC2CCN2C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.0 g of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine and 1.84 g of triethylamine in 100 ml of dry benzene, maintained below 10° C., add 2.08 g of methanesulfonyl chloride. Allow the stirred solution to stand at 6°-10° C. for 2 hours. Add to the mixture, 150 ml of dry dimethyl sulfoxide and 1.40 g of sodium borohydride. Stir at room temperature for 85 hours. Add ether and water, separate the resultant layers, and re-extract the aqueous layer with additional ether. Wash the combined organic phases successively with water and brine, dry over anhydrous sodium sulfate, and remove solvent in vacuo. Chromatograph the resultant oil on 275 g of silica gel, eluting with 1/20 (v/v) ethyl acetate-hexane, to obtain the analytically pure product of this example, m.p. 87.5°-89.5° C.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Br:33])[CH:31]=3)[NH:26][CH:25]=2)O)=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>C(#N)C>[Br:33][C:30]1[CH:31]=[C:32]2[C:24]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=4)=[N:17][CH:18]=3)=[CH:25][NH:26][C:27]2=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncc(Br)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)cn2)cc1

Procedure:
To {5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4-chloro-benzyl)-carbamic acid tert-butyl ester (45, 180.0 mg, 0.33 mmol) in acetonitrile (30.0 mL) were added trifluoroacetic acid (2.0 mL, 0.026 mol) and triethylsilane (4.0 mL, 0.025 mol). The reaction was heated to reflux for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0038, 120 mg, 85.2%). MS (ESI)[M+H+]+=427.2, 429.2.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5](=[N:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6].CN(C)C1CCCCC1.Cl.CN(C)C1CCCCC1>O.C(Cl)Cl>[CH:5]([N:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:1]([Cl:4])=[O:2])=[CH2:6]
Reactant: O=C(Cl)Cl
Reactant: CC=NC(C)(C)C
Agent: Cl
Solvent: CN(C)C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: C=CN(C(=O)Cl)C(C)(C)C
Yield: 80 %

Procedure:
60 parts of phosgene are introduced into 224 parts of methylene chloride. 39.6 parts of ethylidene-tert.-butylamine, 51 parts of dimethylcyclohexylamine and 210 parts of methylene chloride are added to this solution in the course of one hour at from 0° to 5° C., whilst stirring. The mixture is then stirred for 30 minutes, after which the reaction solution is freed from excess phosgene. The mixture is now thoroughly mixed with 250 parts of water at 0° C., whereupon the dimethylcyclohexylamine hydrochloride passes into the aqueous phase. This aqueous phase is separated off and neutralized with sodium hydroxide solution, and the dimethylcyclohexylamine is recovered by distillation. The organic phase is distilled. 52 parts of N-vinyl-N-tert.-butylcarbamoyl chloride (80% of theory) boiling at 85° C./14 mm Hg are obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=O)[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4].Cl.[NH2:34][OH:35]>>[F:1][C:2]([F:31])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12](/[C:13](=[N:34]/[OH:35])/[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4]
Reactant: C[C@]12CC[C@H](SCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Product: C[C@]12CC[C@H](SCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 49.1 %

Procedure:
Following the procedure described in Example 1 and starting from 3β-(3-trifluoroacetamidopropylthio)androstane-6,17-dione (395 mg) and hydroxylamine hydrochloride (65 mg), 3β-(3-trifluoroacetamidopropylthio)-6-(E)-hydroxyiminoandrostane-17-one (200 mg, 50%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.40 (1H, s), 9.42 (1H, t), 3.23 (4H, m), 2.55-0.90 (23H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)O)([O-:3])=[O:2].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[C:27](=[O:30])([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH2:13]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:30][CH2:27][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 1.0 g (6.45 mmol) of 4-nitrocatechol, 4.8 ml (16.1 mmol) of 1-bromotetradecane and 2.5 g (17.4 mmol) of potassium carbonate in 20 ml of acetone and 10 ml of DMF was stirred at reflux under argon for 24 hours. The reaction mixture was filtered while hot and the filtrate was allowed to cool to room temperature and 3.5 g (99% yield, mp 64°-66°) of 3,4-bis(tetradecyloxy) nitrobenzene was obtained by filtration. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].COC(C)(C)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:29])[NH:30][CH2:34][CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.2 %

Procedure:
To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([O-])=[O:7])[N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]1.O1CCOCC1.O.[NH3:23]>O1CCCC1>[C:6]([CH:4]1[CH2:5][S:1][CH2:2][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:7])[NH2:23]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CSCC1C(N)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
3-t-Butyl thiazolidine-3,4-dicarboxylate (2.0 g) was dissolved in tetrahydrofuran (10 ml), and N,N′-carbonyl diimidazole (1.4 g) was added thereto with ice-cooling. The mixture was warmed to room temperature and stirred for 6 hours. 1,4-Dioxane (10 ml) was added thereto, and the mixture was added dropwise to 28% ammonia water (40 ml) cooled on an ice bath. The mixture was warmed to room temperature and stirred for 20 hours. The reaction solution was extracted with ethyl acetate (60 ml). The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give t-butyl 4-carbamoylthiazolidine-3-carboxylate (1.6 g, Y.:81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].Cl.[CH:15](N)=N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:15]=[N:13][S:10](=[O:11])(=[O:12])[C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: N=CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)S(=O)(=O)N=CN2

Procedure:
A suspension of 3.0 g of 2-amino-5-methoxy-benzenesulphonamide is stirred for 1 night at 80° C. in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene. The toluene is evaporated off in vacuo. The residue is taken up in water and the precipitate is filtered off.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([O:56][CH3:57])=[C:51]([CH:55]=1)[C:52](O)=[O:53]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9]/[C:8](=[N:10]\[C:52](=[O:53])[C:51]2[CH:55]=[C:47]([Cl:46])[CH:48]=[CH:49][C:50]=2[O:56][CH3:57])/[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1\oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 13B (1.24 g, 5.53 mmol) in tetrahydrofuran (10 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.06 g, 5.53 mmol), 1-hydroxybenzotriazole (0.85 g, 5.55 mmol), triethylamine (0.45 mL, 3.2 mmol) and 5-chloro-2-methoxybenzoic acid (Aldrich) (1.03 g, 5.55 mmol). The mixture was stirred at 80° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide the title product. MS (ESI+) m/z 393 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (s, 9H), 1.59-1.71 (m, 1H), 1.83-1.97 (m, 2H), 2.02-2.14 (m, 1H), 3.66 (dd, J=14.2, 7.5 Hz, 1H), 3.75-3.82 (m, 1H), 3.82 (s, 3H), 3.82-3.92 (m, 1H), 4.07 (dd, J=14.2, 2.7 Hz, 1H), 4.13-4.24 (m, 1H), 6.52 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.27 (dd, J=9.0, 2.7 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[CH3:16])=[N:6][CH:7]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]Cl)([O-:26])=[O:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][S:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])=[CH:11][C:10]=2[CH3:16])=[N:4][CH:3]=1
Reactant: Cc1cc(N)ccc1Oc1ncc(Cl)cn1
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(NSc2ccccc2[N+](=O)[O-])ccc1Oc1ncc(Cl)cn1
Yield: 83.6 %

Procedure:
2.0 g of 4-(5 chloro-2-pyrimidinyloxy)-3methylaniline and 0.94 g of triethylamine were dissolved in 20 ml of toluene, and a solution of 1.61 g of 2-nitrobenzenesulfenyl chloride dissolved in 5 ml of toluene was dropwise added thereto at room temperature. The mixture was reacted at room temperature for 1 hour under stirring. After completion of the reaction, ethyl acetate was added to the reaction product, and the ethyl acetate layer was washed with water, dried over Glauber's salt and then purified by column chromatography to obtain 2.76 g of N-[4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl]-2-nitrobenzenesulfenamide (Intermediate Compound No. 37) (melting point: 74°-85° C.) in a yellow non-crystalline form.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>O1CCOCC1>[C:1]([NH:5][C:6]([C@@H:7]([NH:8][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH:9]([CH3:10])[CH3:11])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@H](N)C(=O)NC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a solution of L-valine tert-butylamide (1.87 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added 1,3-propanesultone (1.07 g, 9.0 mmol). The solution was stirred at reflux for 5 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×30 mL) and dried in vacuo, affording the title compound (801 mg, 25%). 1H NMR (D2O, 500 MHz) δ ppm 3.43 (m, 1H), 3.00 (m, 2H), 2.85 (m, 2H), 2.03 (m, 3H), 1.21 (m, 9H), 0.92 (d, 3H, J=6.3 Hz), 0.85 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 166.47, 66.55, 52.56, 48.23, 46.11, 29.91, 27.81, 21.29, 18.30, 17.44. [α]D=−11.6° (c=0.0023 in water), ES-MS 293 (M−1).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(OC)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-methoxypyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=463, obsd.=463).