Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:14](=[O:28])[N:15]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:14](=[O:28])[N:15]([CH2:20][C:21]([OH:23])=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)OC(C)(C)C)c2=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)O)c2=O)c1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
HCl gas was bubbled through a stirred suspension of 3-(3-methylphenylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (2.0 g, 5.09 mmol), as prepared in the preceding step, in ethyl acetate (50 mL) at 0° C. until a solution was formed. After warning to room temperature over 2 h, a thick suspension was formed. The mixture was degassed with nitrogen and filtered to give the title compound as a white solid (1.36 g, 80%). 1H-NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.62 (m, 2H), 7.41 (m, 2H), 7.25 (d, 1H, J=8 Hz), 6.09 (d, 1H, J-8 Hz), 4.67 (s, 2H), 2.35 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][NH:4][C:5](=[O:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.Cl>C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5](=[O:21])/[C:6](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:1]/[OH:2]
Reactant: NO
Reactant: CNC(=O)C(=O)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Toluene (20 ml) and a 50% aqueous solution (0.71 ml, 12 mmol) of hydroxylamine were added to N-methyl-2-(2-phenoxyphenyl)-2-oxoacetamide (2.55 g, 10 mmol). The mixture was heated under reflux for 4 hours (E/Z=40/60). After cooling, conc. hydrochloric acid (3.0 ml, 30 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the resulting crystals were separated by filtration, washed with water and toluene and dried to give (E)-N-methyl-2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (2.65 g, Yield: 98.0%, E/Z=98/2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:28]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([N:32]1[CH2:37][CH2:36][CH:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=5)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Reactant: CC(C)(C)N1CCC(=O)CC1
Product: CC(C)(C)N1CCC(Nc2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)CC1

Procedure:
This was similarly prepared from 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide and 1-(t-butyl)piperidin-4-one. MS (ESI) m/z 510.35 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.10 (1H, s), 8.55-8.63 (2H, m), 8.51 (1H, br. s.), 8.30 (1H, s), 7.90 (1H, d, J=8.55 Hz), 7.80 (1H, br. s.), 7.70-7.78 (2H, m), 6.85 (1H, d, J=1.83 Hz), 6.63 (1H, dd, J=8.70, 1.98 Hz), 6.04 (1H, d, J=7.63 Hz), 3.23 (1H, dd, J=10.22, 3.81 Hz), 2.95-3.08 (2H, m), 2.21 (2H, t, J=10.99 Hz), 2.02 (2H, d, J=12.82 Hz), 1.34-1.52 (2H, m), 1.06 (9H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:27])=[O:26]
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(CC#CCN2CCCC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.76 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone and 2.4 ml of triethylamine in 50 ml of dichloromethane was cooled to 0° C. A 1.2 ml portion of methane sulfonyl chloride was added dropwise and the solution was stirred at 0° C. for 1 hour. The mixture was washed with aqueous sodium bicarbonate and brine, dried, concentrated and reconcentrated from toluene. The residue was purified by chromatography (silica gel) to give 1.5 g of (S)-3-[(methanesulfonyl)oxy]-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone as a colorless oil.
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].O=[C:26]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[CH2:27][C:26](=[CH:5][C:1]([O:3][CH3:4])=[O:2])[CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C(CC(=O)OC)CC(=O)OC
Temperature: 120 °C

Procedure:
Carbomethoxymethylenetriphenylphosphorane (167 g, 0.5 mol) in toluene (600 ml) was treated with dimethyl 3-oxoglutarate (87 g, 0.5 mol) and the reaction heated to 100° C. on an oil bath at 120° C. under an atmosphere of nitrogen for 36 h. The reaction was then concentrated in vacuo and the oily residue triturated with 40/60 petrol ether/diethylether 1:1, 600 ml. Triphenylphosphine oxide precipitated out and the supernatant liquid was decanted/filtered off. The residue on evaporation in vacuo was Kugelrohr distilled under high vacuum Bpt (oven temperature 180-200° C. at 0.2 torr) to give 3(methoxycarbonylmethylene)glutaric acid dimethylester in 89.08 g, 267 mM, 53%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:33]([C:32]([F:31])([F:45])[F:46])[CH:34]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.50 g, 0.0012 mol) in DMF (10 mL), was added 3,5-bis (trifluoromethyl)-benzyl bromide (0.50 g, 0.0016 mol) and powdered potassium carbonate (1.55 g, 0.011 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.57 g in 77% yield. 1H NMR (CDCl3) δ 7.61 (s, 1H), 7.50 (s, 2H), 7.24 (m, 12H), 6.83 (d, 1H), 6.62 (s, 1H), 6.59 (dd 1H), 4.19 (t, 1H), 3.68 (s, 2H), 3.67 (s, 3H), 3.60 (t, 2H), 3.56 (d, 2H), 3.14 (d, 2H), 2.64 (t, 2H), 1.83 (t, 2H); 13C NMR (CDCl3) δ 173.3, 160.3, 144.3, 136.7, 132.8, 130.9, 130.1, 129.9, 129.7, 129.5, 128.0, 125.9, 123.7, 122.9, 122.3, 116.2, 114.5, 114.4, 66.6, 61.1, 59.7, 53.4, 52.1, 51.3, 42.6, 28.1.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:3]1.Cl.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][N:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)N)=[CH:17][CH:16]=1>C(O)(C)(C)C>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:20]([CH2:19][C:18]1[CH:29]=[CH:30][C:15]([Cl:14])=[CH:16][CH:17]=1)[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]2=1
Reactant: O=C(O)CC1CCCCC(=O)C1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: O=C(O)CC1CCCCc2c1c1cc(F)ccc1n2Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 1.10 g of 3-oxo-cycloheptaneacetic acid in 35 mL tert-butanol was added 2.13 g of 1-(p-chlorobenzyl)-1-(p-fluorophenyl) hydrazine hydrochloride, The reaction mixture was refluxed under nitrogen for 18 h, cooled to room temperature and then evaporated to dryness. The resultant residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (2X), water (2X) and brine and dried over MgSO4. Filtration and concentration gave oil which was purified by flash chromatography on silica gel. Elution of the column with a mixture of hexane-ethyl acetate (7:3) gave the title compound substituted at the 10-position, mp 138°-139° C. IR (KBr) 1703 cm-1. 'H NMR (CDCl3, 250 MHz) w 1.32-1.54 (m, 1H),2.60-2.87 (m, 2H), 2.65 (d, J=7.5 Hz, 2H), 3.72-3.83 (m, 1H), 5.25 (s, 2H), 6.78-6.88 (m, 1H), 6.81 (d, J=8.0 Hz, 2H), 7.04 (d,d, J=4.5, 9.0 Hz, 1H), 7.20-7.30 (buried m, 1H), 7.23 (d, J=8.0 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:27])[N:25]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CNC(=O)c1csc(N)n1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (380 mg, 1.45 mmol), 2-aminothiazole-4-carboxylic acid (217 mg, 1.5 mmol), HOBt (235 mg, 1.74 mmol), DIPEA (0.303 mL, 1.74 mmol) and EDCI (333 mg, 1.74 mmol) using DCM as solvent using the method of Example 34(d). Yield 92 mg. 1H NMR (400 MHz; CDCl3): δ 1.60 (d, 3H), 3.81 (m, 2H), 4.61 (m, 1H), 4.91 (s, 2H), 6.60 (d, 1H), 7.37 (s, 1H), 7.50 (d, 1H), 7.58 (m, 2H), 7.80 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.C([Li])CCC.Cl>O1CCCC1.O>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:12]([OH:17])[OH:13])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-bromo-4-(difluoromethoxy)-benzene (1.18 g) and triisopropyl borate (1.34 ml) in tetra-hydrofuran (6 ml) was added dropwise n-butyl lithium (1.58 M hexane solution, 3.68 ml) at −78° C. over 10 minutes under argon atmosphere, then the reaction mixture was allowed to warm to room temperature. After being starred at room temperature for 3 hours, the mixture was cooled to 0° C., and thereto were added a 6 N aqueous hydrochloric acid solution and water. The resultant mixture was extracted with ethyl acetate (30 ml) twice, and the combined organic layer was washed with brine (10 ml), dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residual solid was triturated with cold hexane to give the titled compound as a colorless solid. 1H-NMR (DMSO-d6) δ 7.12 (d, J=8.4 Hz, 2H), 7.27 (t, J=74.1 Hz, 1H), 7.83 (d, J=8.6 Hz, 2H), 8.08 (br-s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([SH:20])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.Br[CH2:23][CH2:24][NH2:25].O>C1COCC1>[NH2:25][CH2:24][CH2:23][S:20][C:11]1[NH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]=1
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: NCCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
60% NaH in oil (0.91 g, 22.8 mmol) was added to a suspension of 4,5-diphenyl-2-imidazolethiol (2.5 g, 9.9 mmol) in dry THF (80 ml) at room temperature under stirring. After 15 minutes, 2-bromoethylamine hydrobromide (2.0 g, 9.9 mmol) was added to the mixture. The reaction mixture was refluxed for 1 hour, then poured into water (500 ml) and extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated. The residue was recrystallized (toluene) to give 2-(2-aminoethylthio)-4,5-diphenylimidazole (51.3%): mp 152°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 82 %

Procedure:
As described for Example 40, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (123 mg, 82%) which was obtained as an off-white solid. MS: m/e=365.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].Cl[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[N:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>>[Cl:35][C:29]1[N:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([N:16]3[C:17](=[O:24])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]3[CH:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:26]2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)C(C)C)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 77.5 %

Procedure:
Ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-4-methyl-3-oxopentanoate may be prepared by working in a manner similar to that described in Example 23, but starting with ethyl 4-methyl-3-oxopentanoate (4.7 g), an oily suspension (50% by weight; 1.2 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g). After recrystallization in diisopropyl ether, ethyl 2-[2-(7-chloro-1, 8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-4-methyl-3-oxopentanoate (7 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[Cl:9])[NH2:5].[OH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[OH-].[K+]>CS(C)=O>[Cl:9][C:8]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]([NH2:5])=[CH:3][C:2]=1[N:17]1[CH:18]=[CH:19][C:14](=[O:13])[CH:15]=[CH:16]1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2ccc(=O)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 1.5 %

Procedure:
First, a mixture containing 14.3 g of 3,4-dichloro-6-nitroaniline, 9.01 g of 4-hydroxypyridine, 5.87 g of 86% potassium hydroxide, and 70 ml of dimethylsulfoxide was heated in an oil bath at 130° C. for 3.5 hours, and cooled. Ice water was added to the mixture and precipitated crystals were filtered. Then, 16.9 g of the resultant crude crystals were applied to a column containing 100 g of silica gel and eluted with 10% methanol in chloroform. The eluate was combined and evaporated. The residue was filtered to give 9.78 g of crude crystals of 4-chloro-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline (melting point: 288° to 291° C. (decomposition)). Then, 300 mg of the crude crystals were recrystallized with methanol to give 268 mg of crystals of 4-chloro-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CO[CH:10](OC)[CH2:11][CH:12](OC)OC.O>C(O)(=O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:12]=[CH:11][CH:10]=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1Br
Reactant: COC(CC(OC)OC)OC
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnn2cccnc12
Temperature: 25 °C
Yield: 39 %

Procedure:
A solution of 3-amino-4-bromopyrazole (2.0 g, 12 mmol) and 1,1,3,3-tetramethoxypropane (4.1 mL, 25 mmol) in acetic acid (5 mL) was heated at reflux for 4 h. Water (2 mL) was added and the mixture heated at reflux for a further 0.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated in methanol. The solid thus obtained was washed with cold methanol, ethyl acetate, and hexanes to provide 3-bromopyrazolo[1,5-a]pyrimidine as a brownish solid in 39% yield (0.953 g): 1H NMR (300 MHz, DMSO-d6) δ9.13 (d, J=6.5 Hz, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.19-7.02 (m, 1H); MS (ES+) m/z 197.9 (M+1), 199.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:24])[CH:19]=[N:18][C:17]=2[C:16]([C:30](O)=[O:31])=[CH:15][CH:14]=1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl.CO>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[NH:33][C:30]([C:16]1[C:17]2[N:18]=[CH:19][C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH3:24])=[N:21][C:22]=2[C:13]([C:3]2[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[Cl:12])=[CH:14][CH:15]=1)=[O:31]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Reactant: Nc1ccccn1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccccn3)c3ncc(N(C)CCN(C)C)nc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylic acid (Step 85.1) and 2-aminopyridine. Title compound: ESI-MS: 555.0/557.2 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.42 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:9]([CH2:12][S:13]([CH2:16][CH2:17]O)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:9]([CH2:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)CCO)ccc(Br)c1OC
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Yield: 80.6 %

Procedure:
Methyl 3-bromo-6-(2-hydroxyethanesulphonylmethyl)-2-methoxybenzoate (Intermediate 173, 0.68 g) and methanesulphonyl chloride (0.424 g) were added to a solution of triethylamine (0.561 g) in DCM (10 ml) and the resultant mixture was stirred in an ice bath for 1 hour. DCM was added and the solution was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-40% to give methyl 3-bromo-2-methoxy-6-(vinylsulphonylmethyl)benzoate (0.521 g) as a colourless gum which crystallized on standing to a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:17]([OH:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3]>CN(C=O)C>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:17]([OH:19])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 126.5 %

Procedure:
Alloc-Tyr-OH (38, 5.5 g) was dissolved in DMF (40 mL) and half the volume of DMF was removed under reduced pressure. The residue was cooled at 0° C. under a N2 atmosphere and sodium hydride (60% disperse, 1.9 g) was added in small portions. The suspension was stirred for one hour at 0° C. Then benzyl bromide (1.88 mL) in DMF (5 mL) was added. After one hour at RT 2N hydrochloric acid (7 mL) was added and the mixture concentrated under reduced pressure. To the residue H2O (50 mL) was added, the pH was adjusted to nine using 2N aq. sodium hydroxide and washed with a mixture of toluene and EtOAc. EtOAc was added and the mixture acidified to pH 3 using 2N hydrochloric acid. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified using silica gel column chromatography (DCM/MeOH/AcOH, 89/10/1, v/v/v). The product from the column was dissolved in EtOAc, washed with H2O, dried (Na2SO4) and concentrated to give compound 39 (4.66 g, 77%). Rf 0.5 (DCM/MeOH/AcOH, 89/10/1, v/v/v).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C[O-].[Na+].C(O)C>Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([C:8]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13]=2[OH:21])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(=O)c2sc3ccccc3c2O)cc1

Procedure:
A mixture of 4-cyanophenacyl bromide (3.0 g), methyl thiosalicylate (2.25 g), sodium methoxide (1.52 g) and ethanol (100 ml) was boiled under reflux for 3.5 hours. The mixture was cooled and diluted with 2M hydrochloric acid (100 ml). A precipitate was collected by filtration and recrystallized from ethanol to give 2-(4-cyanobenzoyl)-3-hydroxybenzo[b]thiophene.
Reaction SMILES: NC1C=C(C=C([N+]([O-])=O)C=1C(=O)C1C=CC=CC=1)C(O)=[O:6].N[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([C:31]2[C:30]([N+:41]([O-:43])=[O:42])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=2[OH:6])=[O:40])=[CH:34][CH:35]=1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1
Product: O=C(O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
By replacing in Example 1, step A, 3-amino-4-benzoyl5-nitrobenzoic acid with 3-amino-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid and following the procedure described, 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoic acid is obtained as a hemihydrate with a melting point of 266.5°-267.5° C.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.C[O:10][C:11](=O)[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl>C1COCC1>[C:2]([CH2:1][C:11](=[O:10])[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]1)#[N:3]
Reactant: CC#N
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., CH3CN in THF (1505 uL, 28.82 mmoL) was added dropwise to BuLi (2.5 M in hexane, 11.52 mL) in THF (40 mL). After stirring at −78° C. for 1 h, tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3708 mg, 14.41 mmoL) in THF (10 mL) was added dropwise in 5 min. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h. At 0° C., 1N HCl was added carefully to adjust the pH to about 7. The mixture was then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate.