Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.N[C@@H]1CCCC[C@H]1N.[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:38][CH2:37][CH2:36][C:35]4=[O:39])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:12]=1)[CH3:25]
Reactant: O=C1CCCN1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOCc1nc2cnc3cc(N4CCCC4=O)ccc3c2n1CCCOC(C)C
Temperature: 110 °C

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (0.5 g), copper(I) iodide (0.046 g), (+)-trans-1,2-diaminocyclohexane (0.030 mL), 2-pyrrolidinone (0.122 mL), potassium phosphate (0.55 g) and dioxane (1.2 mL) were added to a 2 dram vial with a stir bar. The vial was flushed with nitrogen, sealed with a Teflon-lined cap, placed in an oil bath, and heated at 110° C. for 16 hours. The reaction was cooled to ambient temperature and then diluted with chloroform and water. The layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with water and saturated aqueous sodium chloride; dried over anhydrous sodium sulfate; filtered and concentrated under reduced pressure. The residue was purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge. The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 80:20. 1-[2-Ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one was isolated as a yellow oil which solidified over time (0.38 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].[CH:24](OCC)(OCC)[O:25][CH2:26][CH3:27]>>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:24][O:25][CH2:26][CH3:27])=[C:3]([S:21]([CH3:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Product: CCOC=Nc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.92 g) in triethyl orthoformate (100 ml) was heated under reflux for two hours, then stirred at 20° C. for 16 hours and evaporated. Trituration with boiling hexane gave 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(ethoxymethylene)amino]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.05 g), m.p.93-95° C. By proceeding in a similar manner the following compound was prepared:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[O:22][N:21]=1>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:14]#[N:15])=[C:16]([CH3:17])[NH:25][C:23]4[O:22][N:21]=[C:20]([CH3:19])[C:24]3=4)[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Reactant: Cc1cc(N)on1
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C)Nc4onc(C)c43)cc12

Procedure:
100 mg (0.42 mmol) (2E)-2-[(3-ethyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 18A) were treated with 3-methyl-1,2-oxazol-5-amine following the procedure described in Example 2. The crude material was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 51 mg (38% of th.) of the racemic title compound.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)(Cl)Cl>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(N2CCCC2)n1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OCc1csc(N2CCCC2)n1
Yield: 4 %

Procedure:
Using the procedure of Example 11C but replacing ethyl 2-(4-morpholinyl)thiazole-4-carboxylate with ethyl 2-(1-pyrrolidinyl)thiazole-4-carboxylate provided, after silica gel chromatography using 2-4% methanol in chloroform, the desired compound (Rf 0.26, 4% methanol in chloroform) in 53% yield. 1H NMR (CDCl3) δ2.04 (m, 4H), 2.75 (br, 1H), 3.45 (m, 4H), 4.56 (s, 2H), 6.32 (s, 1H). Mass spectrum: (M+H)+ =185.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>O>[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:2]2[CH:3]=[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:23]1
Reactant: O=S(=O)(Nc1cc(Cl)nn2ccnc12)c1ccccc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(NS(=O)(=O)c3ccccc3)c3nccn3n2)CC1
Reaction time: 72 h

Procedure:
To N-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide (100 mg, 0.325 mmol) from 1a was added trans-1,4-diaminocyclohexane (1000 mg, 8.77 mmol). The mixture was allowed to melt at 165° C. for 3 days. The melt was then cooled, water was added followed by extraction with dichloromethane. The organic layer was then concentrated in vacuo and purified by preparative HPLC. This gave 4.5 mg (2%) of the title compound as a TFA salt. 1H NMR (500 MHz, MeOH-D3) δ ppm 7.97 (2H, d, J=5 Hz), 7.85 (1H, s), 7.71 (1H, s), 7.63 (1H, m), 7.56 (2H, m), 6.63 (1H, s), 3.64 (1H, m), 3.12 (1H, m), 2.23-2.04 (4H, m), 1.51 (2H, m), 1.34 (2H, m). LC/MS m/e 387 (MH+). HPLC, 1.60 min. Waters Sunfire C18 4.6×50. 0%-100% B. B: 90% MeOH, 10% H2O, 0.1% TFA. A: 10% MeOH, 90% H2O, 0.1% TFA.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:25][C@H:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29]>>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([NH:25][C@H:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C

Procedure:
Fragment I was prepared by stepwise chain elongation using the mixed anhydride procedure at -15° C. with careful temperature control. As seen in the scheme of FIG. 2 mixed anhydride (M.A.) coupling (isobutylchloroformate) of Z-Glu(OtBu)-OH with H-Asn-OtBu provided Z-Glu(OtBu)-Asn-OtBu. Catalytic hydrogenation (10% Pd-C) of this compound cleaved the N-terminal protective group and the dipeptide was coupled to Z-Ala-OH using mixed anhydride coupling to give Z-Ala-Glu (OtBu)-Asn-OtBu. The N-terminal was again deprotected by catalytic hydrogenation and the tripeptide coupled with Z-Glu(OtBu)-OH to give the protected tetrapeptide Z-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu which is deblocked by catalytic hydrogenation to provide the desired protected tetrapeptide (1).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]2[NH:27][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=3[N:26]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: N=C(N)COCCc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2ccc(F)c(Cl)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 82.2). Off-white solid. MS: m/e=352.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31]O)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31][Br:54])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CS(=O)(=NCCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=NCCBr)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a stirring suspension of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-[2-hydroxy-ethyl]sulfoximide (0.6 g, 0.00118 mol) in DCM (6 mL) was added triphenyl phosphine (460 mg, 0.00177 mol) followed by carbon tetrabromide (589 mg, 0.00177 mol) at 25-30° C. Reaction mixture was stirred at same temperature for 3 hr. Subsequent work up and column purification (100-200 mesh silica gel, 10-50% ethyl acetate in hexane) gave 300 mg of titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][O:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:19]=2[CH3:18])[CH2:10][C@@H:9]1[CH2:14][CH2:15][O:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: COCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1C(=O)OC(C)(C)C
Yield: 80.8 %

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine (0.179 g, 0.73 mmol), 2,3-dimethylbenzoic acid (0.115 g, 0.75 mmol), HOBT (0.098 g, 0.73 mmol), EDC.HCl (0.153 g, 0.80 mmol) in methylene chloride (5 mL). Triethylamine was added to adjust the pH to 7. Chromatography on silica gel with 40% ethyl acetate in hexane afforded the title compound as a clear oil (0.222 g). NMR (CDCl3, 300 MHz) δ 6.9-7.2 (5H, m), 4.70 (1H, m), 3.8-4.5 (9H, mm), 2.0-2.3 (6H, mm), 1.9 (2H, m), 1.59 (9H, s).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:22]2[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:23]2[C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:22]2[CH2:26][C@H:25]([O:27][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:24][C@H:23]2[C:28](=[O:37])[N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH3:30])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Under nitrogen atmosphere, the tert-butyldimethylsilyl chloride was added to a solution of compound 50 (750 mg, 1 eq.) and TEA (537 μL, 1 eq.) in DCM (6 mL). The reaction mixture was stirred overnight at room temperature and quenched with water. The organic layer was washed with brine, dried on sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 51 in 70% yield.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].O.C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>O>[NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(N)C(=O)O
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Product: CC(C)(C)[C@@H](N)C(=O)O
Temperature: 28 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
(DL)-tert-Leucine (15 g, 0.1145 mol) was dissolved in water (180 mL). To the solution was added dibenzoyl-d-tartaric acid monohydrate (21.5 g, 0.057 mol) and stirred for 24 hours at 28° C. (±3). The reaction mixture was filtered to collect L-tert-leucine dibenzoyl-d-tartrate salt. The filtrate was reserved for isolating D-tert-leucine later. The tartrate salt was added to water (150 mL) followed by concentrated sulphuric acid (3 mL) and stirred for 4 hours. Liberated dibenzoyl-d-tartaric acid was collected and dried (19.8 g, 92% yield). The filtrate was washed with diisopropyl ether (50 mL) to remove any traces of dibenzoyl-d-tartaric acid, cooled to 5° C. and treated with a saturated solution of barium hydroxide till the pH was neutral. It was filtered to remove the precipitated barium sulphate. The filtrate was concentrated under reduced pressure to remove all the solvent. The residue obtained was stirred with acetone (15 mL×2), filtered and dried to obtain colorless solid L-tert-leucine (6 g, 80% yield, 99% chemical purity, 99.9% chiral purity).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][CH2:20][S:21][C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:41])[N:4]([CH3:42])[C:3]1=[O:43].BrC1C=C(C=C([Cl:53])C=1)C#N>>[Cl:53][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([C:10]2[N:9]([CH2:19][CH2:20][S:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:8]=[C:7]3[C:6]=2[C:5](=[O:41])[N:4]([CH3:42])[C:3](=[O:43])[N:2]3[CH3:1])[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Cl)cc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cc(Cl)cc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate GA step 1) by replacing bromobenzonitrile with 3-bromo-5-chlorobenzonitrile;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[I:14]Cl.C([O-])(O)=O.[Na+]>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][C:3]=1[I:14]
Reactant: Nc1ccc(C(=O)C(F)(F)F)cc1
Reactant: ClI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(C(=O)C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-2,2,2-trifluoroethanone (1.0 g, 5.28 mmol) in 1M aqueous HCl solution (70 mL) was added iodine monochloride (0.77 g, 4.76 mmol). The reaction mixture was stirred at r.t. for 2 h, then basified with the addition of aqueous sat. NaHCO3 solution and extracted with EtOAc (2×100 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 15-20% EtOAc/hexanes) gave the title compound (0.983 g, 59%) as a cream solid. δH (CDCl3) 8.40 (1H, d, J 1.0 Hz), 7.92-7.85 (1H, m), 6.76 (1H, d, J 8.6 Hz), 4.91 (2H, br. s). LCMS (ES+) RT 2.86 minutes (Method 3).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[Br:14]Br.C(=O)(O)[O-].[Na+]>[Fe].ClCCl>[Br:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:12])[S:5][CH2:4][CH2:3][C:2]2([CH3:13])[CH3:1]
Reactant: Cc1ccc2c(c1)SCCC2(C)C
Reactant: BrBr
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.2 g (32.2 mmol) of 4,4,7-trimethylthiochroman, 40 ml of dichloromethane and 90 mg of iron powder are introduced into a three-necked flask. 1.65 ml (32.2 mmol) of bromine are added and the mixture is stirred at room temperature for two hours. The reaction medium is poured into sodium bicarbonate solution and extracted with dichloromethane, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with heptane. 5.9 g (67%) of the bromo derivative are collected in the form of a pale yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[C:21]([CH:22]=O)=[C:20]([Cl:24])[N:19]=[CH:18][N:17]=1>CO>[Cl:15][C:16]1[C:21]([C:22]2[NH:12][C:10]3[CH:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:7]=[C:8]([CH3:14])[C:9]=3[N:13]=2)=[C:20]([Cl:24])[N:19]=[CH:18][N:17]=1
Reactant: Cc1cc(-n2ccnc2)cc(N)c1N
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CO
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3Cl)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (180 mg, 0.96 mmol) in methanol (4 mL) was added a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (183 mg, 0.96 mmol) in methanol (1 mL). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (5% methanol/CH2Cl2) to yield the title compound (180 mg, 55%). LCMS (M+H)+ m/z 344 (t=1.31 min.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][O:26][N:27]=[C:28]1[C:32]2([CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)[CH2:31][NH:30][CH2:29]1.C(#N)C>C(N(CC)CC)C>[C:39]([O:38][C:36]([N:34]1[CH2:35][C:32]2([C:28](=[N:27][O:26][CH3:25])[CH2:29][N:30]([C:16]3[N:17]=[C:18]4[C:13]([C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:20])[CH2:31]2)[CH2:33]1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
110 mg of 1-(2,4-difluorophenyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 120 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and thereto 0.5 ml of triethylamine was added dropwise. The resulting mixture was stirred for 4 hours at 50° C. and then for 2 hours at the room temperature. The precilitated solid was filtered and dried to give 150 mg of the titled compound(yield: 79.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:26][OH:27].C(N(CC)CC)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]([NH:26][OH:27])=[NH:5]
Reactant: Cc1nc(C2(C)CCCCC2)oc1COc1ccc(C#N)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(C2(C)CCCCC2)oc1COc1ccc(C(=N)NO)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
1.24 g 2-Chloro-4-[4-methyl-2-(1-methyl-cyclohexyl)-oxazol-5-ylmethoxy]-benzonitrile were dissolved in a mixture of 20 ml tetrahydrofuran and 20 ml methanol. 5.0 g hydroxylamine hydrochloride were added followed by the addition of 10.0 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 1.39 g 2-Chloro-N-hydroxy-4-[4-methyl-2-(1-methyl-cyclohexyl)-oxazol-5-ylmethoxy]-benzamidine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:22])[N:5]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:6]2=[O:11].[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:4](=[O:22])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[C:6]2=[O:11])=[CH:13][CH:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)c1ccc(N2C(=O)c3cccc(N)c3C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(N2C(=O)c3cccc(NCc4ccncc4)c3C2=O)cc1
Reaction time: 1 h

Procedure:
In a 25 mL round bottomed flask, 4-amino-2-(4-tert-butyl-phenyl)-isoindole-1,3-dione (30 mg, 0.101 mmol, Step B) was dissolved in 1,2-dichloroethane (10 mL). To this was added 4-pyridinecarboxaldehyde (0.05 mL, 0.524 mmol). The reaction was stirred for 1 h under N2. NaBH(OAc)3 (40 mg, 0.188 mmol) was added and the suspension was stirred for 6 h. The reaction was quenched with saturated NaHCO3 solution (50 mL). The reaction was rotary evaporated to remove the 1,2-dichloroethane. The product was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford an oil. The oil was purified by flash chromatography on silica gel eluting with 30% EtOAc in hexanes. MS (ES+): 386.1 (M+H)+. Calc'd for C24H23N3O2-385.46.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40].[Br:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[N:46][CH:47]=1>C1COCC1>[Br:41][C:42]1[CH:43]=[C:44]([O:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][C:36]2=[O:40])[CH:45]=[N:46][CH:47]=1
Reactant: O=C1CCCN1CCO
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCN1CCOc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of triphenylphosphine (3 g, 12 mmol) in THF (20 mL) at 0° C. was added the following reagents in order in 10 minutes interval: diethyl azodicarboxylate (2 ml, 12 mmol), 1-(2-hydroxyethyl)pyrrolidin-2-one (0.9 ml, 8 mmol), and 5-bromopyridin-3-ol (2 g, 12 mmol). After 20 min, ice bath was removed; the reaction mixture was warmed up to rt and stirred for 20 h. The reaction was stopped, and solvent was removed The crude product was purified using SiO2 chromatography with hexanes:acetone (70%:30%) solvent system to afford the product as white solid. Wt: 900 mg. MS (ESI pos. ion) m/z: 286.3. Calc'd exact mass for C11H13BrN2O2: 285.14. 1H NMR (300 MHz, chloroform-d) δ ppm 2.04 (none, 1H) 2.41 (d, J=16.37 Hz, 2H) 3.51-3.62 (m, 2H) 3.71 (t, J=5.19 Hz, 2H) 4.16 (t, J=5.19 Hz, 2H) 7.37 (d, J=1.90 Hz, 1H) 8.23 (s, 1H) 8.31 (s, 1H).