Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:21])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:15]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
Methyl 2-(2-(4-iodophenyl)acetamido)-4-methylthiophene-3-carboxylate (420.4 mg, 1.01 mmol), 4-pyridylboronic acid (Aldrich, 167 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol), and potassium carbonate (565 mg, 4.1 mmol) were combined in DME (2 mL) and water (1 mL) in a sealed tube, and heated to 80° C. over 17 h. The reaction mixture was cooled to rt, then partitioned between EtOAc and water. The organic layer was separated, washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography (EtOAc/hexanes) afforded the titled compound. 1H NMR (CDCl3) δ11.3 (s, 1H), 8.67 (dd, J=4.7, 1.4H, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.60-7.40 (m, 4H), 6.38 (s, 1H), 3.88 (s, 2H), 3.80 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3) δ167.7, 166.6, 150.3, 149.9, 147.8, 137.4, 134.8, 134.6, 130.3, 127.7, 121.5, 113.0, 112.3, 51.5, 43.5, 17.8; MH+ 367.1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[H-].[Na+].[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH2:21][CH2:22][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=[C:6]1[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:15])[CH3:19]
Reactant: CN(C)CCCc1nc2ccccc2[nH]1
Reactant: CCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(CCCN(C)C)nc2ccccc21
Temperature: 60 °C

Procedure:
Grams 6 2-(3-dimethylaminopropyl)benzimidazole in 100 ml N,N-dimethylformamide are treated with 1.8 g 60% sodium hydride, the mixture is warmed up to 60° C. and 4 g 2-ethoxyethyl chloride are added thereto. It is maintained at 60° C. for 5 hours, then it is poured into water, extracted with diethyl ether and the extracts washed thoroughly with water, filtered on charcoal, made anhydrous on sodium sulphate and evaporated to dryness. The residue is chromatographied on silica gel column eluting with chloroform:methyl alcohol (9:1) and it gives 1-(2-ethoxyethyl)-2-(3-dimethylaminopropyl)benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:17](OC(=O)C)(=O)[CH3:18]>>[CH3:17][C:18]1[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[N:5][CH:6]=2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncncc1C(=O)Nc1ccccc1
Product: Cc1nc2ncncc2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Compound 23 (70.0 mg, 0.32 mmol) was mixed with 6 mL of acetic anhydride and the reaction mixture was stirred at 120° C. for 2 h while monitored by MS. The reaction mixture was then concentrated in vacuo to yield 75 mg of crude compound 24 which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25](O)=[O:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:25]([C:17]3[N:16]([CH3:15])[C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:26])[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2csc(NC(=O)c3cc4ccccc4n3C)n2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1 g of 2-amino-4-(4-methoxyphenyl)thiazole is dissolved in 20 ml of dimethylformamide and, successively, 0.6 g of 1-methylindole-2-carboxylic acid, then 1.6 g of 1-benzotriazolyl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and then 0.7 g of triethylamine are added to the reaction mixture at ambient temperature. The reaction mixture is left at ambient temperature for about 12 hours, while stirring well, before pouring into 100 ml of ice-water; the aqueous phase obtained is then extracted with twice 50 ml of ethyl acetate. The organic extracts are dried over anhydrous magnesium sulphate and evaporated to dryness. The residual solid is purified by chromatography on a silica column (eluant: CH2Cl2). Yield
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]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CCCS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CCCS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(propylsulfonyl)benzene. MS (ESI): mass calcd. for C19H18FN3O2S, 371.11; m/z found, 372.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.14 (d, J=1.2, 1H), 8.08 (dd, J=7.8, 1.1, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.72 (m, 1H), 7.48 (dd, J=7.4, 1.1, 1H), 7.38 (dd, J=12.4, 1.4, 1H), 7.32 (dd, J=8.0, 1.6, 1H), 2.94-2.81 (m, 2H), 1.49-1.32 (m, 2H), 0.79 (t, J=7.4, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][CH2:12][O:13][C:14]([N:16]=[C:17]=[S:18])=[O:15]>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:17]([NH:16][C:14](=[O:15])[O:13][CH2:12][CH3:11])=[S:18])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1cnc(Cl)nc1N
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)Nc1nc(Cl)ncc1OC
Temperature: 15 °C

Procedure:
2-Chloro-5-methoxypyrimidin-4-amine (1) (6.4 g, 0.040 mol) was suspended in ethyl acetate (100 mL) and heated to near reflux. Ethyl isothiocyanatidocarbonate (8.9 g, 1.7 eq) was added all at once, and the mixture was maintained at reflux for 10 hours. The resulting slurry was cooled to 15° C., and the solid product was isolated by filtration and the cake washed with fresh ethyl acetate to afford the title compound in several crops as a solid (7.8 g, 67%): mp 182° C.; 1H NMR (DMSO-d6): δ 11.97 (s, 1H), 11.72 (s, 1H), 8.50 (s, 1H), 4.22 (q, 2H), 3.72 (s, 3H), 1.17 (t, 3H); 13C NMR (DMSO-d6): δ 177.82, 153.58, 150.00, 149.01, 144.26, 142.63, 62.76, 57.56, 14.44; Mass spec (accurate mass): Calcd for C9H11ClN4O3S: 290.024039; found, 290.0241.
Reaction SMILES: [C:1]([S@:5](/[N:7]=[C:8](/[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)\[CH2:9][CH2:10][N:11]([C@H:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:20])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH2:33]1[CH2:37]OC[CH2:34]1>>[CH3:22][C:21]([CH3:24])([CH3:23])[C@@H:19]([N:11]([CH2:10][CH2:9][C@@:8]([NH:7][S@@:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:37][CH:33]=[CH2:34])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH3:20]
Reactant: C1CCOC1
Reactant: C[C@H](N(CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Agent: [Br-]
Product: C=CC[C@](CCN(C(=O)OC(C)(C)C)[C@@H](C)C(C)(C)C)(N[S@](=O)C(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (E)-3-((R)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl((S)-3,3-dimethylbutan-2-yl)carbamate (800 mg, 1.76 mmol) in THF (10 mL) was added allymagnesium bromide (1 M, 6 mL, 5.29 mmol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl (S)-3,3-dimethylbutan-2-yl((R)-3-((R)-1,1-dimethylethylsulfinamido)-3-(4-fluorophenyl)hex-5-enyl)carbamate (870 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([CH3:18])[C:7]1=[O:11]
Reactant: COc1ccccc1C=C1CCNC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C=C1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate 3-(2′-methoxybenzylidene)-2-pyrrolidone (5.0 g) obtained in Example 317 was dissolved in dimethylformamide (50 ml) and sodium hydride (0.99 g) was added thereto under ice-cooling. The mixture was stirred at room temperature for 30 min. Methyl iodide (1.72 ml) was added under ice-cooling and the mixture was stirred for 8 hr at room temperature. After completing of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:18][C:19]1([CH3:25])[CH2:24][O:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1([CH3:25])[CH2:24][O:23][CH2:22][CH2:21][N:20]1[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: CC1(C)COCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)COCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (80 mg, 0.305 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (2 mL) was added 3,3-dimethylmorpholine (46.2 mg, 0.305 mmol, commercially available, for example from Otava, Kiev, Ukraine or Tyger Scientific, Ewing, USA) and triethylamine (0.127 mL, 0.914 mmol). The reaction mixture was then heated to 120° C. for 50 min in a microwave reactor. The reaction mixture was concentrated in vacuo and the crude product was purified by MDAP. The relevant fractions were combined and concentrated in vacuo. The product was dissolved in DCM and 1N HCl in ether (110 uL) was added. The mixture was concentrated in vacuo, triturated with ether, then dried in vacuo to yield the title compound (white crystals, 40 mg).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]([P:32](Cl)(Cl)=[O:33])([CH3:31])([CH3:30])[CH3:29]>CCCCCC.C1CCCCC1>[C:28]([P:32]1(=[O:33])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][N:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)P(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CC(C)(C)P1(=O)c2ccccc2CN1c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 8.2 %

Procedure:
Under a static nitrogen atmosphere at 26° C., a solution of n-butyllithium (3.93 g, 7.13 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. The reaction mixture was cooled to 0° C. and then a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2.5 hours at 26° C. and then cooled to 0° C. A solution of t-butylphosphonic dichloride (5.6 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension and the resulting mixture was stirred for 1.5 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 10 ml. of a saturated solution of ammonium chloride. The resulting mixture was concentrated in vacuo and the residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then with water, dried over sodium sulfate and concentrated in vacuo to yield a red oil. The red oil was separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was triturated with isopropyl ether and petroleum ether to yield a white solid. The white solid was recrystallized from isopropyl ether to yield 1-(t-butyl)-2-pheny-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 8% yield) as colorless needles having a melting point of 171°-172° C. and the following analysis:
Reaction SMILES: [OH:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a mixture of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0° C. was added NaH (60 wt %) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3 h. It was then cooled to 0° C. and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.02-5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94-3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53-1.42 (m, 11H), 1.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[C:3]([CH:8]=[N:11][OH:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ncccc1F
Temperature: 0 °C
Yield: 77 %

Procedure:
Combine 3-fluoropyridine-2-carboxaldehyde (3.00 g, 0.024 mol) with hydroxylamine hydrochloride (1.70 g, 0.026 mol) and ice (50 g) in an ethanol/water (30 mL/30 mL) mixture. Add aqueous sodium hydroxide (2.46 g, 0.06 mol, in 25 mL of water) dropwise and stir for 4 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extract with diethyl ether. Dry over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using methanol/dichloromethane to give 2.59 g (77%) of the desired oxime as an off white solid. MS(ES): (M+1)+ 140.9, 142.0 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](O)=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH2:37])([CH3:36])([CH3:35])[CH3:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](=[O:29])[NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CCC(=O)CC2C(=O)O)OC1(C)C
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.1 %

Procedure:
A solution of 4-Benzyl-5-(2-carboxy-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.66 g, 3.74 mmol) in dry dichloromethane (20 ml) was stirred at 0° C. during sequential treatment with tert-butyl amine (1.4 ml, 12.7 mmol), 1-hydroxybenzotriazole hydrate (570 mg, 5 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (970 mg, 5 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for 20 hours and then concentrated in vacuo. The crude mixture was dissolved in ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexane: 1/3 to 4/6) provided 4-benzyl-5-(2-tert-butylcarbamoyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.2 g, 61%). Mass spectrum 502 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCN(C)C)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(2-dimethylamino-ethyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N,N-dimethyl-1,2-ethanediamine in an analogous manner to Example 1396. Product isolated as a yellow foam (32 mg, 59%). LCMS (m/e) 538 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.22 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.61 (d, 1H, J=7.7 Hz), 7.47-7.41 (m, 1H), 7.38 (s, 1H), 7.30-7.16 (m, 2H), 7.14-7.07 (m, 1H), 7.06-7.00 (m, 2H), 3.65-3.55 (m, 4H), 3.38 (s, 3H), 3.04-2.92 (m, 4H), 2.89-2.78 (m, 6H), 2.64 (t, 2H, J=5.7 Hz), 2.36 (s, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:4]
Reactant: CNCCc1[nH]c2ccccc2c1-c1ccccc1
Reactant: O=C(Cl)CCl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCc1[nH]c2ccccc2c1-c1ccccc1)C(=O)CCl
Reaction time: 0.5 h

Procedure:
A solution of 17.5 ml chloroacetyl chloride in 100 ml chloroform is added dropwise within 15 minutes to a solution of 50.1 g N-methyl-3-phenyl-1H-indol-2-ethanamine and 30.7 ml triethylamine in 500 ml chloroform. After 30 minutes the mixture is made alkaline with aqueous ammonia. The organic phase is separated, washed with water and dried. Evaporation of the solvent gives the heading compound, m.p. 135°-138° (from methylene chloride/ether).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[O:17][CH3:18])/[C:13]([NH2:15])=[O:14])(=O)C.[CH3:19]N.CO>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH:15][CH3:19])=[O:14]
Reactant: CN
Reactant: CO/N=C(/C(N)=O)c1ccccc1COC(C)=O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of (E)-2-(2-acetoxymethylphenyl)-2-methoxyiminoacetamide (432 mg), 40% methylamine/methanol solution (5 ml) and methanol (5 ml) was stirred at 60° C. for 16 hours in a sealed tube. After the mixture was cooled by allowing it to stand, the solvent was evaporated under reduced pressure. The resulting residue was crystallized from ethyl acetate-hexane. The crystallization mother liquor was concentrated under reduced pressure and purified by column chromatography on silica gel (ethyl acetate:hexane=4:1) to obtain the title compound (379 mg, yield: 98.3%, white crystals) as a mixture of the E- and Z-isomers (E/Z≠93/7 determined by 1H-NMR analysis).
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38]Br>C(#N)C>[N:1]([C:4]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][O:36][CH3:35])=[CH:18][CH:19]=2)=[N:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3]
Reactant: COCCBr
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(O)cc2)c1N=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1ccc(-c2nc(-c3ccc(OC)cc3)cc(C(=O)OC)c2N=[N+]=[N-])cc1
Temperature: 75 °C
Yield: 43.7 %

Procedure:
A mixture of methyl 3-azido-2-(4-hydroxyphenyl)-6-(4-methoxyphenyl)isonicotinate (83 mg, 0.221 mmol), cesium carbonate (359 mg, 1.10 mmol), and 2-bromoethyl methyl ether (0.062 mL, 0.662 mmol) in acetonitrile (1 mL) was heated at 75° C. for 5 hr. The reaction was partitioned between EtOAc and water. The organic phase was separated and washed with brine, dried with sodium sulfate and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 0 to 30% EtOAc) afforded 42 mg of methyl 3-azido-2-(4-(2-methoxyethoxy)phenyl)-6-(4-methoxyphenyl)isonicotinate as an oil. MS (ESI) m/z 435.1 (M+H). 1H NMR (CDCl3) δ ppm 8.02 (2H, d, J=8.55 Hz), 7.93 (1H, s), 7.78-7.86 (2H, m), 7.05 (2H, d, J=8.85 Hz), 6.98 (2H, d, J=8.85 Hz), 4.16-4.24 (2H, m), 4.02 (3H, s), 3.85 (3H, s), 3.75-3.81 (2H, m), 3.47 (3H, s).