Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[OH:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:20][O:21][CH3:22])[CH2:17][CH:18]=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:17][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:15])[CH2:20][O:21][CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: COCC(O)(CC=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaB(OAc)3 (0.98 g), and acetic acid (0.27 mL) were added in the given order to a solution of 3-hydroxy-4-methoxy-3-phenyl-butyraldehyde (0.90 g) in tetrahydrofuran (20 mL) at ca. 10-15° C. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Then, water (50 mL) and 1 M aqueous NaOH solution (20 mL) were added and the resulting mixture was stirred for another 30 min. The mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. After drying (MgSO4), the solvent was removed to give the title compound which was submitted to the subsequent reaction step without further purification. Yield: 1.80 g (quantitative).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH:9]1[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>CC(O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([N:11]2[CH2:12][CH:9]([N:7]([CH3:8])[C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10]2)[CH:20]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2cc(Cl)ncn2)C1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
Azetidin-3-yl-methyl-carbamic acid tert-butyl ester (1.97 g, 11 mmol) in IPA (5 mL) was added dropwise to a stirred solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) in IPA (20 mL) followed by dropwise addition of TEA (2.11 mL, 15.1 mmol) at ambient temperature under N2. The resulting milky yellow solution was heated to 80° C. and maintained at 80° C. for 2 hours. The solution was allowed to cool and evaporated to give a yellow oil. The crude material was partitioned between DCM (70 mL) and water (30 aqueous extract was re-extracted with DCM (70 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate (30 mL), dried (MgSO4), filtered and evaporated to give a coloured oil. The crude oil was purified by flash column chromatography on silica gel eluting with DCM:MeOH (99:1 changing to 96:4 by volume) to yield the title compound as a solid (1.93 g, 64%).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[NH2:14][C:15]1[N:20]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=[C:17]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[CH:16]=1>CN(C=O)C>[CH2:22]([S:21][C:19]1[N:18]=[C:17]([NH:29][C@H:30]([CH3:33])[CH2:31][O:32][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:16]=[C:15]([NH2:14])[N:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(N)nc(SCc2ccccc2)n1
Reaction time: 24 h

Procedure:
Imidazole (0.29 g) was added to a solution of tert-butyldimethylsilyl chloride (0.34 g) and the subtitle product of step i) (0.6 g) in DMF (10 ml). The reaction was stirred for 24 h before addition of a further equivalent of tert-butyldimethylsilyl chloride and imidazole. After stirring for an additional 24 h the reaction mixture was partitioned between EtOAc (100 ml) and H2O (200 ml). The aqueous was extracted further with EtOAc (3×100 ml), the organics combined, washed with H2O (100 ml), brine (100 ml), dried (MgSO4) and concentrated to a crude solid. This material was purified by column chromatography (1:1 Et2O/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 0.50 g.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]#[N:30]>C1COCC1.C1COCC1.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]#[N:30]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (15.8 mg of a 60% dispersion in mineral oil, 0.411 mmol) in dry THF (2 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.06 g, 0.294 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 4-chloro-3-cyano-benzenesulfonyl chloride (97.1 mg, 0.411 mmol) in dry THF (3 ml). Stirring continued at 0° C. for 15 minutes and then the reaction mixture is poured onto water (30 ml) and extracted with ethyl acetate (100 ml). The organic portion is separated and washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 404)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](O)=O)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH4+:16].[OH-]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]3[NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=4[N:16]=3)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)cn1
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Brc1cccc(-n2cnc(-c3nc4ccccc4[nH]3)c2)c1
Temperature: 200 °C
Yield: 38 %

Procedure:
1-(3-Bromo-phenyl)-1H-imidazole-4-carboxylic acid 5 (150 mg, 0.56 mmol) was added to PPA (preheated to 140° C.) and the mixture was stirred until a thick homogeneous solution was obtained. 1,2-Phenyldiamine (67 mg, 0.62 mmol) was added and the mixture was heated for 6 h at 200° C. After cooling to room temperature it was carefully diluted with 6% NH4OH aqueous solution until the pH=8. The precipitate formed was isolated by filtration, dissolved in little ethyl acetate and filtrated again. Concentration of the organic layer afforded 72 mg (38%) of the title compound as a purple solid. HRMS (ESI+): m/z=339.1949 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].O[CH2:12][C@@H:13](N)[CH2:14]C(C)C.OCCN.C(=O)C(C)C>>[CH:13]([CH:1]1[NH:5][C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:3][O:2]1)([CH3:14])[CH3:12]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](N)CO
Agent: CC(C)C=O
Solvent: NCCO
Product: CC(C)C[C@H]1COC(C(C)C)N1

Procedure:
(L)-Leucine methyl ester was reduced to (1S)-1-(hydroxymethyl)-3-methylbutylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCl2 and SO2Cl2 according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to Method C7b to afford (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-oxazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1cccc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
To a stirred solution of 2.99 g (8.90 mmole) of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 27 mL of acetone and 27 mL of water was added 2.97 g (45.15 mmole) of sodium azide. The mixture was heated at 70 degrees for 11 hours. The mixture was partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 60 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.97 g of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark brown oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>CS(C)=O>[C:11]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1
Yield: 72.5 %

Procedure:
A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75° C. overnight. The mixture was poured into water (10 L) and extracted with EtOAc (7 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford N-tert-butyl-4-nitroaniline (1 g, 73%). 1H NMR (CDCl3, 400 MHz) δ 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
Reaction SMILES: O=[C:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH2:20]([C:2]1[N:32]=[C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]2[CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCc1ccccc1)CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: c1ccc(CCc2cn3c(n2)-c2ccccc2Nc2ncccc2-3)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g, 1 eq.) in acetic acid (10 mL) was added ammonium acetate (3.37 g, 10 eq.). The reaction was stirred at 120° C. for 8 hours. The reaction mixture was poured onto water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-10% methanol in dichloromethane) gave the 2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.374 g, 27%). 1H NMR (CDCL3) 400 MHz δ 8.08 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.97 (dd, JA=8.0 Hz, JB=1.2 Hz, 1H), 7.46 (dd, JA=8.0 Hz, JB=1.6 Hz, 1H), 7.34-7.15 (m, 6H), 7.08 (td, JA=7.6 Hz, JB=1.2 Hz, 1H), 6.98 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 6.86 (dd, JA=7.6 Hz, JB=0.8 Hz, 1H), 6.81 (s, 1H), 6.27 (s, 1H), 3.07-2.90 (m, 4H); LCMS: 339 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.C[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]1)=[O:28]
Reactant: CNCCCCO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 43.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 4-methylamino-butan-1-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4%). HRMS (ES+) m/z Calcd for C27H33Cl2N3O2+H [(M+H)+]: 502,2023. found: 502.2020.
Reaction SMILES: N#N.[CH3:3][NH:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:12].[CH2:13](C(CC)(CC)C([O-])([O-])[O-])[CH3:14]>C(O)C>[CH3:3][N:4]1[C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]=[C:13]1[CH3:14]
Reactant: CNc1c(N)cccc1F
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: N#N
Solvent: CCO
Product: Cc1nc2cccc(F)c2n1C

Procedure:
Following the procedure of Preparation O-1, 3.0 g of N2 -methyl-3-fluorophenylenediamine and 3.9 ml of triethylorthoacetate in 100 ml of ethanol gave 3.0 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([F:34])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([F:34])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cn(C(CC(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
80 mg (151 μmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoyl}amino)benzoate (racemate) in 2 ml of methanol/water (4/1) were reacted with 326 mg (302 μmol) of caesium carbonate according to General Method 4. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 18 mg (23% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:25]=3[O:34][CH2:35][CH2:36][CH2:37][OH:38])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:39](O)(=[O:41])[CH3:40].O>CN(C=O)C>[OH:38][CH2:37][CH2:36][CH2:35][O:34][C:25]1[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:22]1[C:13]([NH:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN)cc2)c(OCCCO)c(OC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CNC(C)=O)cc2)c(OCCCO)c(OC)c1
Yield: 41 %

Procedure:
100 mg of 4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide (content 82%), 37 mg of DAPECI and 8.7 l of acetic acid in 1 ml of DMF are stirred at RT overnight in a screw-cap vial. The reaction solution is poured into water, and the deposited precipitate is filtered off with suction. Purification by preparative HPLC on silica gel RP18 (acetonitrile, water) gives a total of 39 mg of N-(4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}benzyl)acetamide (yield 41%); MS-FAB (M+H+)=582.2; Rf (polar method): 2.19 min.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH:13]=2)=[CH:4][C:3]1=[O:21].[ClH:22].O1CCOCC1>CCOC(C)=O>[ClH:22].[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][C:3]1=[O:21].[ClH:22]
Reactant: Cn1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1ccc(C2=CCNCC2)cc1=O
Temperature: 25 °C

Procedure:
A solution of tert-Butyl 1′-methyl-2′-oxo-1′,2′,3,6-tetrahydro-4,4′-bipyridine-1(2H)-carboxylate (100 mg, 0.3 mmol) in AcOEt (2 mL) was treated with 4 M of hydrogen chloride in 1,4-dioxane (0.1722 mL, 0.6888 mmol). The mixture was stirred at r.t. 2 h., and concentrated under reduced pressure to afford the desired compound as HCl salt which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=191.1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[C:24]4[O:23][CH2:22][O:21][C:20]=4[C:19]([C:25]#[C:26][CH2:27][O:28][CH3:29])=[CH:18][C:17]=3[Cl:30])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:30][C:17]1[CH:18]=[C:19]([C:25]#[C:26][CH2:27][O:28][CH3:29])[C:20]2[O:21][CH2:22][O:23][C:24]=2[C:16]=1[NH:15][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[C:6]([O:31][CH3:32])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: CN1CCNCC1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCl)c(OC)cc23)c2c1OCO2
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCN4CCN(C)CC4)c(OC)cc23)c2c1OCO2
Yield: 17 %

Procedure:
7-(2-Chloroethoxy)-N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-6-methoxyquinazolin-4-amine (0.2 g, 0.4 mmol) was dissolved in 1-methylpiperazine (4 ml) and heated at 50 C for 12 hours. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography on alumina eluting with a mixture of 0-10%, methanol in dichloromethane to give the product as a white solid (0.037 g, 17%). NMR Spectrum: (CDCl3) 2.28 (s, 3H), 2.50 (s(broad), 4H), 2.63 (s(broad), 4H), 2.94 (t, 2H), 3.44 (s, 3H), 4.01 (s, 3H), 4.33 (t, 2H), 4.36 (s, 2H), 6.08 (s, 2H), 6.78 (s, 1H), 7.04 (s, 1H), 7.05 (s, 1H), 7.25 (s, 1H), 8.63 (s, 1H). Mass Spectrum: M+H+ 540 and M+H−]538.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][NH:1][CH2:2][CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: NCCc1ccccn1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCCc3ccccn3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 7 h

Procedure:
2-(2-Aminoethyl)pyridine (8.13 mmol) and tetrabutylammonium iodide (0.010 g, 0.027 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.7 g, 1.62 mmol) in dry methanol (10 mL). The reaction mixture was stirred at 110° C. for 7 h in an atmosphere of nitrogen. It was concentrated and treated with a methanolic HCl solution (10 mL), refluxed overnight, concentrated, treated water and 10% aqueous sodium bicarbonate solution to pH 7. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.225 g, (26.81%). 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.0-3.10 (m, 6H, 3CH2), 3.40-3.55 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.45 (t, 1H, NH), 6.80 (s, 1H, Ar), 6.83 (s, 1H, Ar), 7.30-7.50 (m, 3H, Ar), 7.80 (t, 1H, Ar), 8.20 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS (CI+): m/e 516 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:29]([CH2:28][CH2:27][O:26][CH3:25])[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Reactant: COCCC(=O)Cl
Product: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(6-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152–156. 3-Methoxypropionyl chloride was used in Part C. The crude product obtained in Part D was recrystallized from acetonitrile. The crystals were washed with cold acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[CH:15]=[C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[CH2:20][CH2:21][C:16](=[CH:15][C:14]2[CH:13]=[C:12]([CH:31]=[CH:30][CH:29]=2)[O:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:33])([F:1])[F:32])=[CH:10][N:9]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.36 g, 0.77 mmol) in CH2Cl2 (3 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.46 mL, 5.97 mmol). The resulting mixture was stirred for 2 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organic extract was dried over Na2SO4, and concentrated under reduced pressure to give the title compound (0.282 g, 99%). m/z (365.1, M+ H+).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+:16].[CH2:17](Br)[CH2:18][CH:19]([CH3:21])[CH3:20]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:16].[CH2:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)CCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCC(C)C)C(=O)OCC
Reaction time: 0.83 h

Procedure:
Sodium ethoxide was prepared from sodium metal (9.1 g) and freshly distilled absolute ethanol (250 ml). Diethyl malonate (63.5 g) was added to sodium ethoxide in ethanol, and the mixture was stirred at 60°-70° C. for 50 min. Isoamyl bromide (60 g) was added, and the reaction mixture was heated under reflux overnight. After the usual work-up, the resulting crude product was distilled under reduced pressure to give diethyl isoamylmalonate. Yield: 71.7 g (78%).