Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]([F:22])([F:21])[C:6]1[N:11]=[C:10]([N:12]2[CH2:16][C@@H:15]3[C:17](=[O:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)[CH:9]=[CH:8][CH:7]=1>CCOCC>[CH3:1][C@:17]1([OH:20])[C@@H:15]2[C@@H:14]([CH2:13][N:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:5]([F:4])([F:21])[F:22])[N:11]=3)[CH2:16]2)[CH2:19][CH2:18]1
Reactant: O=C1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@H]12
Reactant: C[Mg]I
Solvent: CCOCC
Product: C[C@@]1(O)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reaction time: 1 h

Procedure:
Methylmagnesium iodide in ether (0.302 mL, 0.907 mmol) was added to (3aR,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]hexahydrocyclopenta[c]pyrrol-4(1H)-one (70 mg, 0.259 mmol) from Example 32 in ether (0.1 mL) at 25° C., and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic washes were purified by silica gel chromatography using 0-30% ethyl acetate/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.46 (t, J=7.9, 1H), 6.93 (d, J=7.2, 1H), 6.50 (d, J=8.6, 1H), 5.92 (s, 1H), 4.03 (dd, J=11.1, 3.7, 1H), 3.69 (t, J=9.4, 1H), 3.61-3.50 (m, 1H), 3.43 (dd, J=10.0, 5.7, 1H), 2.83-2.69 (m, 1H), 2.46 (td, J=9.0, 3.9, 1H), 2.14-2.02 (m, 1H), 1.90 (dq, J=11.6, 8.4, 1H), 1.79-1.62 (m, 2H), 1.42 (s, 3H); MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32])=[O:19])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Temperature: 4 °C
Reaction time: 48 h

Procedure:
2.26 g of the p-nitrophenyl ester of benzyloxycarbonyl-L-asparagine and 1.89 ml (13.6 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 900 mg (3.9 mmol) of (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid hydrochloride in 15 ml of dimethylformamide, and the mixture was stirred at 4° C. for 2 days. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with 1N aqueous hydrochloric acid to cause crystallization. The crystals were collected by filtration and washed first with water and then with ethyl acetate, to give 1.52 g of the title compound as colorless crystals, melting at 225°-227° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[C:13]([O:16][C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:21])[CH2:3][CH2:2]1.O[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].[O:28]1[CH2:33]CC(=O)C[CH2:29]1>CN(C)C(=O)C>[O:21]=[C:8]1[N:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:23]3([C:24]#[N:25])[CH2:27][CH2:33][O:28][CH2:29][CH2:26]3)[CH2:2][CH2:3]2)[C:11]2[CH:12]=[C:13]([O:16][C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:15][C:10]=2[NH:9]1
Reactant: CC(C)(O)C#N
Reactant: O=c1[nH]c2ccc(OC(F)(F)F)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Solvent: CC(=O)N(C)C
Product: N#CC1(N2CCC(n3c(=O)[nH]c4ccc(OC(F)(F)F)cc43)CC2)CCOCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-piperidin-4-yl-6-(trifluoromethoxy)-1,3-dihydro-2H-benzimidazol-2-one (D32, 301 mg), 2-hydroxy-2-methylpropanenitrile, (160 mg), tetrahydro-4H-pyran-4-one (200 mg) magnesium sulphate (600 mg) and N,N-dimethylacetamide (1 ml) were stirred at 60° C. under a slow stream of argon overnight. The resulting white paste was partitioned between dichloromethane and water and sonicated. The dichloromethane layer was separated, dried by passing through a 3 g hydromatrix cartridge. (Large proportion of the material was lost due to spillage). The solvent was removed and the title compound was obtained as a white solid from ether. Yield 62 mg. M+ 411.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]([OH:53])=[CH:41]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:41]2[C:40]3[C:45](=[CH:46][C:47]([O:48][CH3:49])=[C:38]([O:37][CH3:36])[CH:39]=3)[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]=2[OH:53])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: COCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(COC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (84 mg, 0.29 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol SMA 44012 (73 mg, 0.29 mmol) followed by a 2 N aq. LiOH solution (0.29 mL, 0.58 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL) and the mixture was stirred for 5 min at room temperature and concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol dihydrochloride 67 as a yellow solid (9 mg, 6% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:8]([C:16]([O:18][CH3:19])=[O:17])[S:7][C@H:6]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:4].O1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC1C=C(N=C=O)C=CC=1>[CH3:19][O:18][C:16]([C@H:8]1[S:7][C@@H:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:9]2[CH:10]=[CH:31][CH:30]=[C:29]([CH3:28])[CH:8]=2)=[O:4])[C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17]
Reactant: C1CCOC1
Reactant: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CN)[C@H]1c1ccccc1
Agent: Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1

Procedure:
The process is performed in a similar manner to that described in Example 1, but starting with a solution containing 0.7 g of tert-butyl (2S,4S,5S)-3-(2-aminoacetyl)-5-methoxycarbonyl-4-phenyl-2-thiazolidinecarboxylate in 20 ml of tetrahydrofuran and 250 μl of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (20/80 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.28 g of tert-butyl (2S,4S,5S)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-phenyl-2-thiazolidinecarboxylate is thus obtained in the form of a white foam, Rf=0.39 [ethyl acetate/cyclohexane (50/50 in volume)]; 1H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 297 K, δ in ppm): 1.48 (s, 9H: CH3 of the tert-butyl); 2.21 (s, 3H: ArCH3); 3.28 and 4.15 (broad d and d respectively, J=17.5 Hz, 1H each: COCH2N); 3.37 (s, 3H: COOCH3); 5.10 (d, J=7 Hz, 1H: H at C5 of the ring); 5.43 (s, 1H: H at C2 of the ring); 5.68 (d, J=7 Hz, 1H: H at C4 of the ring); 6.70 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.06 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); from 7.00 to 7.50 (mt, 5H: aromatic H); 7.72 (mt, 2H: H ortho to the phenyl).
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].[CH:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:3])[CH3:4]
Reactant: CCCCCCC=O
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.66 ml of glacial acetic acid are added dropwise to the ice-cooled mixture of 5.0 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2one hydrochloride, 15.2 g of heptaldehyde, 2.52 g of sodium cyanoborohydride and 53 ml of acetonitrile. The mixture is stirred at room temperature for 2 hours, cooled, acidified to pH=1 with concentrated hydrochloric acid and evaporated to remove the acetonitrile. The residue is diluted with water, the solution washed with diethyl ether, basified to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with chloroform. The extract is dried, evaporated and the residue crystallized from ethanol-water (5:2) to give the 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 102°-104°.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[CH3:12][S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].[O:22]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:12][S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:37][CH2:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[O:11])[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COC(=O)c1cccnc1Cl
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Product: CS(=O)(=O)N1CCN(c2ncccc2C(=O)NCCc2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The title compound was prepared in analogy to example 1, but starting from 2-chloro-nicotinic acid methyl ester and subsequently using 1-methanesulfonyl-piperazine in the first step and 2-(4-phenoxy-phenyl)-ethylamine in the third step. MS (ISP): 481.1 ((M+H)+.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1ccc(F)cc1C(=O)Nc1ccccc1Cl
Yield: 57.7 %

Procedure:
Prepared according to Procedure A using 2-amino-5-fluorobenzoic acid (1.0 g, 6.45 mmol) and SOCl2 (1.2 mL, 16.1 mmol) in benzene (30 mL), followed by 2-chloroaniline (1.4 mL, 12.9 mmol) and CHCl3 (30 mL). The product was triturated from CH2Cl2 to provide 985 mg of a mustard-yellow solid (58%). 1H NMR (CDCl3) δ: 7.66 (dd, J=2.9, 8.7 Hz, 1H); 7.52-7.55 (m, 1H); 7.32-7.37 (m, 3H); 7.09 (dt, J=3.0, 8.5 Hz, 1H); 6.71 (dd, J=4.3, 8.7 Hz, 1H). MS (ES): m/z 305.0 (M+40).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15]OCC.C(OC(=O)C)(=O)C>>[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CCOC=C(C(=O)OC)[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 45 h
Yield: 51 %

Procedure:
A 4-l. battery jar was charged charged with 641 g (4.23 moles) of 6-chloroindole, 926 g (5.3 moles) of crude (ca. 85% pure) alpha-nitro-beta-ethoxy acrylic acid methylester and 475 g (4.65 moles) of acetic anhydride. The mixture was well stirred at room temperature for 45 hours to give a highly viscous suspension of an orange precipitate. 1.5 l of a mixture of benzene-ether-hexane 1:1:3 was added and the mixture stirred vigorously for 30 minutes. The product was collected by filtration, washed with 1:0 l of the same solvent mixture and dried at room temperature and 16 mmHg to constant weight to afford 600 g (51%) of product as orange crystals, m.p. 159°-160°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:3]=2)=[CH:31][N:30]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ncc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(C(F)(F)F)c2)cn1
Yield: 60.2 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 2-methoxy-5-pyrimidineboronic acid (0.066 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.064 g) as a colorless solid. MS (ISP): 498.4 (M+H)+
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(O)CC(C)C>[Cu].CCOCC.O>[C:16]([C:15]1[CH:24]=[CH:25][C:12]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[C:13]([N+:26]([O-:28])=[O:27])[CH:14]=1)(=[O:17])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(Nc2ccccc2C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A mixture of anthranilic acid (1.37 g, 10 mmol.), 4-chloro-3-nitrobenzophenone (2.88 g, 11 mmol.), anhydrous potassium carbonate (powder, 2.77 g, 20 mmol.), copper (powder, 50 mg), and isoamyl alcohol (25 mL) was stirred and heated for one hour under reflux. The reaction mixture was cooled to room temperature, and stirred for 15 minutes after addition of water (30 mL) and ether (30 mL). The insoluble red-brown solid was collected by filtration and washed with water and ether. The red-brown solid mainly comprising a potassium salt of the desired compound was suspended in water (40 mL). To the suspension was added 2M hydrochloric acid until an aqueous portion of the suspension showed approximately pH 2. The suspension was vigorously stirred for one hour at room temperature. The deposited crystalline precipitate was collected by filtration and washed with several portions of water and ether. The washed precipitate was placed under reduced pressure at 60° C. for 3 hours to dryness. Thus, 2.34 g (65%) of the desired compound was obtained as a yellow-orange crystalline product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[H][H]>C(O)C.O1CCCC1.[Pd]>[CH3:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1cccnc1C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cccnc1CCc1ccc(N)cc1
Yield: 91.4 %

Procedure:
A mixture of 3-methyl-2-[2-(4-nitrophenyl)vinyl]pyridine (13.0 g) in ethanol (250 ml), tetrahydrofuran 250 ml) and acetic acid (13 ml) was hydrogenated over 10% palladium on carbon (3 g) under atmospheric pressure of hydrogen gas for 7 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the resultant solution was adjusted to pH 7.0 with aqueous 20% potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from diethyl ether and diisopropyl ether to give 3-methyl-2-[2-(4-aminophenyl)ethyl]pyridine (10.5 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1>>[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([N:10]4[CH2:9][CH2:8][N:7]([CH2:6][C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[CH2:12][CH2:11]4)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1
Reactant: c1csc(CN2CCNCC2)c1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(Cc2cccs2)CC1

Procedure:
Reaction of N-(2-thienylmethyl)piperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g) analogously to the procedure of Example 4 gave the title compound after suspending in methanol as the dihydrochloride salt; yield 3.50 g (95%), m.p. 244°-245° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31]O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:31][CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(O)c2)c(=O)n1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCNC(=O)OC(C)(C)C)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 47 h
Yield: 25 %

Procedure:
To a mixture of 200 mg of 4-hydroxy-3-[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, 10 ml of tetrahydrofuran, 170 mg of N-(t-butoxycarbonyl)-2-aminoethanol and 276 mg of triphenylphosphine was added dropwise 414 μl of diethyl azodicarboxylate (40% toluene solution), and this was stirred at room temperature for 47 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 75 mg of 4-hydroxy-3-[3-[3-[N-(t-butoxycarbonyl)-2-aminoethoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (54a)].
Reaction SMILES: CC(C)([O-])C.[Na+].CO[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH2:26][C:27]#[N:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:9]=[C:26]([C:17]1[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:16]=1[Cl:15])[C:27]#[N:28]
Reactant: N#CCc1ccc(C(F)(F)F)cc1Cl
Reactant: COC=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC=C(C#N)c1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of sodium tert-butoxide (3.28 g, 34.2 mmol) in tetrahydrofuran (20 mL) at 0° C. was added a solution of methyl 3-methoxyacrylate (2.65 g, 22.8 mmol) and (2-chloro-4-trifluoromethyl-phenyl)-acetonitrile (5.00 g, 22.8 mmol) in tetrahydrofuran (20 mL) dropwise over 45 minutes. The red solution was stirred at 0° C. for 3 hours and then allowed to warm to 10° C. over another 2 hours. The reaction was then treated with 0.2 M aqueous citric acid (50 mL) and extracted with a 2:1 mixture of methyl tert-butyl ether and hexanes (75 mL). The organic layer was washed with an aqueous saturated solution of sodium chloride (50 mL). The organic solution was passed through a short column of silica gel, washing the residual material through the pad with additional methyl tert-butyl ether. The filtrate was concentrated in vacuo to afford 4-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-but-3-enoic acid methyl ester as a red oil (6.74 g, 97%). Major olefin isomer: 1HNMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.58 (d, 1H, J=8.3), 7.49 (d, 1H, J=8.3), 6.89 (t, 1H, J=7.1), 3.78 (s, 3H), 3.69 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) δ 169.4, 145.9, 136.1, 133.7, 133.0 (q, J=33.5), 131.5, 127.6 (q, J=3.8), 124.5 (q, J=3.8), 123.2 (q, J=292), 115.4, 114.7, 52.7, 36.7; IR (ATR, neat) 2957, 2224, 1740, 1438, 1395, 1319, 1268, 1172, 1128, 1080, 1010, 963, 892, 831, 719, 655 cm−1. Minor olefin isomer: 1H-NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.61 (d, 1H, J=7.8), 7.43 (d, 1H, J=7.8), 7.02 (t, 1H, J=7.8), 3.71 (s, 3H), 3.11 (d, 2H, J=7.8).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1([F:21])[CH2:19][CH:18]([OH:20])[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:20][CH:18]2[CH2:19][C:16]([F:21])([F:15])[CH2:17]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: OC1CC(F)(F)C1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c([N+](=O)[O-])c1
Yield: 97.1 %

Procedure:
1.0 g of Methyl 4-fluoro-3-nitrobenzoate, 1.6 g of 3,3-Difluoro-cyclobutanol, and 3.3 g of Cs2CO3 were stirred in 10 ml of anhydrous DMF for 7 h at 60° C. The reaction mixture was then poured into 100 ml of water and extracted three times using 30 ml of EA each. The organic layer was dried using MgSO4 and volatiles were evaporated to yield 1.4 g of the title compound that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:22][NH:23][OH:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:23]([OH:24])[CH3:22])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Reactant: CNO
Agent: Cl
Product: CN(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ; 12.00 (br s, 1H), 8.91 (s, 1H), 8.03 (s, 1H), 7.91 (d, 1H, J=2.8 Hz), 7.38 (dd, 2H, J=5.7 Hz, J=8.5 Hz), 7.12 (d, 2H, J=8.5 Hz), 6.71 (d, 1H, J=3.0 Hz), 5.59 (s, 2H), 3.33 (s, 3H). LCMS (API-ES, M+H+): 301.1. HRMS calcd for C16H15FN3O2 (M+H) 300.1148. found 300.1138. HPLC: 100% purity