Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(C(N)=O)C3C=CC=CC=3C(=O)CC=2C=1.[CH3:20][O:21][C:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[CH:23]=1.[C:37](Cl)([Cl:39])=[O:38]>>[CH3:20][O:21][C:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]([C:37]([Cl:39])=[O:38])[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[CH:23]=1
Reactant: O=C(Cl)Cl
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Product: COC1=Cc2ccccc2N(C(=O)Cl)c2ccccc21

Procedure:
U.S. Pat. No. 3,642,775 assigned to Ciba-Geigy Corporation, claims Oxcarbazepine specifically and discloses the process for the preparation of Oxcarbazepine, wherein 10-methoxy-5H-dibenz[b,f]azepine is reacted with phosgene gas to give 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride and ammonolysis of the resultant compound to give the amide followed by hydrolysis to give Oxcarbazepine.
Reaction SMILES: [CH2:1]([S:16][CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:16]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])=[O:31])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCS(=O)C(CC)C(=O)O
Temperature: -20 °C
Reaction time: 0.58 h
Yield: 47.6 %

Procedure:
2-((3Z,6Z,9Z,12Z)-Pentadeca-3,6,9,12-tetraenylthio)butanoic acid (0.20 g, 0.62 mmol) was dissolved in dry CHCl3 (10 mL) and the solution was cooled down to −20° C. under inert atmosphere. mCPBA (˜77%, 0.15 g, 0.68 mmol) dissolved in dry CHCl3 (2 mL) was added dropwise and the resulting solution was stirred at −20° C. for 35 minutes. The solvents were evaporated in vacuo, the residue was added heptane (10 mL) and the resulting white precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was added heptane (10 mL). The resulting white precipitate was again removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (heptane:EtOAc+w/1% HCOOH 4:1-1:1). Concentration of the appropriate fractions afforded 100 mg (48% yield) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[C].[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2F)[nH]c1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 18.3 %

Procedure:
To a solution (80 mL) of ethyl 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (8.6 g) in ethanol was added 10% palladium carbon (50% containing water, 0.86 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 36 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (70 mL), 10% palladium carbon (50% containing water, 0.90 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 60 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1→5:1) to give the title compound as a brown solid (yield 1.37 g, 18%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[CH2:7]([O:9][C:10](=[O:22])[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12])[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:7]([O:9][C:10](=[O:22])[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:2][CH2:3][N:4]([CH3:6])[CH3:5])[CH:14]=1)=[O:12])[CH3:8]
Reactant: CN(C)CCCl
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCN(C)C)c2ccccc12
Yield: 61.7 %

Procedure:
The general procedure 1 was then followed using 1-chloro-2-dimethylaminoethane (6 mmol, 0.65 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6 mmol, 1.3 g) and Cs2CO3 (6.6 mmol, 2.15 g). The purification was achieved by column chromatography (petrolether:ethylacetate:diethylamine 6:3:1) to yield ethyl-2-{1-[2-(dimethylamino)-ethyl]-1H-indol-3-yl}-2-oxoacetate (3.7 mmol, 62%) as pale yellow crystals. Mp=71-72° C. IR {tilde over (ν)} [cm−1]=3139; 3044; 2977; 2946; 2797; 2772; 1727; 1641. EI-MS m/z (rel. int.)=288 (19.15%; M+•.). 1H NMR (300 MHz, CDCl3) 8.45 (m; 2H; indole-H); 7.37 (m; 3H; indole-H); 4.41 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.26 (t; 3J=6.9 Hz; 2H; indole-CH2CH2N); 2.76 (t; 3J=6.9 Hz; 2H; indole-CH2CH2N); 2.31 (s; 6H); 1.44 (t; 3H; 3J=7.1 Hz; OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:29])[CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:49])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:29])[CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3C)c3ccc(Cl)cc3F)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: Cc1cc(F)ccc1C(c1ccc(Cl)cc1F)c1c[nH]c2c(CS(C)=O)cccc12

Procedure:
The title compound was prepared starting from 100 mg (0.23 mmol) of the compound from Example 287 in analogy to the synthesis of the compound from Example 296. 99 mg (95% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH:5]=1.C([NH2:22])=O.C[O-].[Na+]>CN(C=O)C.CO>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:22])=[O:2])[CH2:11][CH2:12]1)[CH2:17][CH3:18]
Reactant: CCCN1CCC(c2cccc(C(=O)OC)c2)CC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C(N)=O)c2)CC1

Procedure:
A solution of 3-(1-Propyl-piperidin-4-yl)-benzoic acid methyl ester (0.6 g) and formamide (320 μL) in DMF (9 ml) was heated to 100° C. under a blanket of argon. Sodium methoxide in methanol (30%, 770 μL) was added dropwise and after 1 h, GC analysis revealed the complete absence of starting material and indicated the titled compound as the sole product. After cooling, CH2Cl2 was added and the resulting solution was filtered through a pad of celite and evaporated to dryness. The residue was chromathographed on a silica column using MeOH:CH2Cl2 (1:3 (v/v)) as eluent. The fractions containing pure titled compound were collected, and the solvent was removed in vacuum, affording 400 mg of the titled compound. m.p. 182° C. (oxalate) (MS m/z (rel. intensity, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17](=[O:19])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
In a 30 gallon stainless steel unit, 55 L of Dowtherm A (a eutectic mixture of diphenyl and diphenyl ether) was stirred and heated at reflux (253°-257° C.) for one hour. To this was added a solution of 31.3 kg diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate in 10 L Dowtherm A held at 94°-98° C. The addition was effected over a period of four hours so that reflux of the reaction mixture was maintained. The reaction mixture was then allowed to cool and crystallization of the product began. After the temperature had reached 28°-30° C., the solid product was collected on a ceramic filter and washed with 2×9 L dimethylformamide (DMF). The damp filter cake was added to 65 L DMF in a 30 gallon kettle. The resulting slurry was heated at 90°-95° C. for 30 minutes and then cooled to 40° C. The solid was collected on a ceramic filter, washed with 2×8 L DMF and dried at 60° C. for 24 hours to give 23.8 kg ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate containing about 10% of the 5-chloro-6-fluoro isomer as indicated by NMR spectra.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].SC1C=CC=CN=1.ClC1C([O:24][C:25](=O)[C@H:26]([CH:38]([CH3:40])[CH3:39])[NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=C(Cl)C(Cl)=C(Cl)C=1Cl>ClCCl>[CH2:1]([NH:8][C:25](=[O:24])[C@H:26]([CH:38]([CH3:39])[CH3:40])[NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Sc1ccccn1
Agent: [Na]
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
1.1 ml. of benzylamine is dissolved in 200 ml. of dichloromethane, and 0.13 g. of the sodium salt of 2-mercaptopyridine is suspended therein. Then, 5.0 g. of benzyloxycarbonyl-L-valine pentachlorophenyl ester is added thereto. As determined by thin layer chromatography, the period required to consume one-half of the reactants is about 10 minutes. After 3 hours, treatment is effected in the same manner as in the previous example, and the dichloromethane layer is concentrated, whereby 3.1 g. of crude crystals are obtained (yield: 91%). By recrystallization from ethyl acetate, 2.7 g. of needle-like crystals are obtained. m.p. 174.5°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)#[N:2].[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:14])=[CH:10][CH:9]=1)[CH:17]1[CH2:18][CH2:19][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:21][CH2:22]1)#[N:2]
Reactant: C1CNCCN1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Yield: 34.5 %

Procedure:
Using general procedure E, 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 131) (60 mg, 0.11 mmol) and piperazine (29 mg, 0.33 mmol) afforded COMPOUND 134 as a white solid (23 mg, 34%). 1H NMR (CDCl3) δ 0.98-1.18 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.51-1.55 (m, 1H), 1.70-1.82 (m, 3H), 2.18 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.58 (t, 1H, J=11.1 Hz), 2.76-2.92 (m, 7H), 3.26-3.33 (m, 1H), 3.58-3.72 (m, 5H), 3.87 (m, 3H), 6.51 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.03-7.08 (m, 1H), 7.23-7.26 (m, 2H), 7.42-7.47 (m, 3H), 7.55 (d, 1H, J=6.6 Hz), 8.26 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.55, 29.41, 30.70, 31.42, 40.14, 43.98, 46.66, 48.43, 52.45, 56.42, 60.83, 112.64, 113.03, 119.29, 124.40, 127.70, 128.79, 129.72, 130.18, 131.01, 131.12, 134.51, 139.03, 141.94, 149.74, 170.22, 171.00. ES-MS m/z 607 (M+H). Anal. Calcd. for C37H46N6O2.CH2Cl2: C, 70.10; H, 7.36; N, 13.12. Found. C, 69.89; H, 7.48; N, 13.02.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6].C[Si]([C:32]#[CH:33])(C)C.CCN(CC)CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6])#[CH:33]
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)Nc2cc(-n3cnc(C)c3)cc(C(F)(F)F)c2)ccc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In a pressure tube with one end sealed, add 485 mg 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (1.0 mmol) from Step 2, 500 mg trimethylsilylacetylene (5.0 mmol), 19 mg Cu I (0.1 mmol), 7 mg Pd(PPh3)2Cl2 (0.01 mmol), 1.0 mL Et3N in 3.0 mL acetonitrile, and after Nitrogen replacement, the mixture is stirred at 80° C. for 2 h. After cooling to room temperature, the solution was filtered by 2 cm silica gel column. The filtration is washed three times with ethyl acetate and is concentrated to brown solid which is further dissolved in 5 mL methanol. The solution is then added with 980 mg K2CO3 and stirred at room temperature for 3 h. The solid was filtered off and the solution was concentrated to column chromatography f 344 mg desired product. (90%)
Reaction SMILES: [NH:1]1[C:5]2[NH:6][CH:7]=[CH:8][C:9](=O)[C:4]=2[CH:3]=[N:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>O=P(Cl)(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][N:2]=[CH:3][C:4]=12
Reactant: O=c1cc[nH]c2[nH]ncc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 53396.2 %

Procedure:
1,7-Dihydro-pyrazolo[3,4-b]pyridin-4-one (1.2 g, 8.8 mmol) (Dorn, H. et al., Prakt. Chem., 324, 55762 (1982)) in POCl3 (15 ml) at 0° C. was treated with PCl5 (2.5 mg, 0.01 mmol). The solution was allowed to warm to rt over 1 h, then heated to 90° C. and held 3 h. The solution was-concentrated under reduced pressure, then treated with ice and water (50 ml). The resulting mixture was extracted with ethyl acetate (100 ml), and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (30 ml). The organic layer was dried over MgSO4, then evaporated under reduced pressure to give 4-chloro-1H-pyrazolo[3,4-b]pyridine as a yellow solid (820 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 857 (d, 1H, J=5.2 Hz), 8.25 (s, 1H), 7.28 (d, 1H, J=5.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[BrH:11].BrBr.C(OCC)C>C(O)(=O)C>[BrH:11].[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cncc(C)c1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cncc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 183.3 %

Procedure:
300 mg (2.22 mmol) of 1-(5-methylpyrid-3-yl)ethanone are dissolved in 15 mL of glacial acetic acid. 365 μl (2.22 mmol) of hydrobromic acid and 126 μl (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(5-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ether and dried. The 600 mg of product obtained have the following characteristics:
Reaction SMILES: Cl[C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50]/[C:2](=[C:21]2\[C:22](=[O:36])[N:23]([C:33](=[O:35])[CH3:34])[C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:3]2[CH:8]=[CH:7][C:6]([CH2:9][N:10]3[C:14](=[O:15])[C:13]4=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]4[C:11]3=[O:20])=[CH:5][CH:4]=2)=[CH:48][CH:47]=1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 2c from 3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone, 4-tert.butoxycarbonylaminomethyl-aniline and triethylamine in dichloromethane.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7][NH:6]1>C(O)C.[Pd]>[ClH:1].[OH:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7][NH:6]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(CCO)NCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C(CCO)NCC2
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.18 g, 8.43 mmol) in ethanol (100 ml) was added 10% Pd-C (0.4 g) and the solution hydrogenated on the Parr Hydrogenator for 2 h. The reaction mixture was filtered to remove the catalyst and the filtrate reduced to about 1/3 of the volume. The solution was warmed and ether (150 ml) was added. The precipitate was collected to give the title compound as a yellow solid (1.81 g, 94%), mp. 199.5-200.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:4]=1[O:5][CH2:6][CH:7]([OH:22])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])=[O:12])#[N:2].Cl>O1CCOCC1>[O:12]=[C:11]1[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[N:10]1[CH2:9][CH2:8][CH:7]([OH:22])[CH2:6][O:5][C:4]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCC(O)CCNC(=O)c1ccccc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc([N+](=O)[O-])cc1OCC(O)CCN1C(=O)c2ccccc2C1=O

Procedure:
2-(4-(2-cyano-5-nitrophenoxy)-3-hydroxybutylcarbamoyl)benzoic acid was reacted as described in Intermediate Y(3) with hydrogen chloride in dioxane to get 2-(4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutoxy)-4-nitrobenzonitrile which is used as-is in the next step. LC-MS (M+Na)+=404.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]>[Zn].CC(O)=O>[CH3:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[CH:2]2
Reactant: Cc1ccc2ncc(C#N)c(Cl)c2n1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc2ncc(C#N)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 4-chloro-6-methyl-[1,5]naphthyridine-3-carbonitrile (200.0 mg, 0.98 mmol) (compound 5, see Example 1)in AcOH (20 mL) was added Zinc dust (156.1 mg, 2.40 mmol) and the reaction mixture was stirred at r.t. for 2 hrs. The reaction mixture was filtered through celite and the filtrate was then concentrated. The residue was dissolved in AcOEt and washed with water, Sat. Na2CO3, brine and dried to yield 6-methyl-[1,5]naphthyridine-3-carbonitrile as a light brown solid (120.0 mg, 71.3%). HR-MS-EI (+) m/e calcd for C10H7N3(M+) 169.0640. found 169.0639.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(N3CCCCC3)cc21
Product: CC1c2cc(N3CCCCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-piperidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([O-])(=O)C.[Na+].[Br:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[Br:18][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Reaction time: 0.83 h
Yield: 92 %

Procedure:
3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g, 4.07 mmol) were stirred in acetic acid (5 cm3) then bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm3) was added drop-wise to the reaction mixture. The reaction was stirred for 50 min., then poured into water. The mixture was basified with sodium carbonate, extracted with ethyl acetate (×3), dried (MgSO4), filtered, and evaporated to give the subtitled compound (0.89 g, 92%) 1H NMR (DMSO-d6) δ 1.21 (s, 6H), 6.76 (d, 1H, J=8.22 Hz), 7.29 (dd, 1H, J=2.12 Hz, 8.23 Hz), 7.49 (d, 1H, J=2.03 Hz), 10.4 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCOCCOCCO
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a stirred solution of alcohol (9) (4.86 g, 33.2 mmol, 1.0 equiv.) in THF (70 mL) was carefully added NaH (60%, 1.60 g, 40.0 mmol, 1.2 equiv.) in small portions at room temperature. The reaction was then refluxed for 1 h (until H2 release ceased) then cooled to 0° C. Methyl bromoacetate (3.8 mL, 40.1 mmol, 1.2 equiv.) was then added dropwise. After 15 min at 0° C., the reaction was submitted to a EtOAc/H2O extraction. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered then evaporated under reduced pressure. Purification was achieved by distillation under high vacuum and provided 4.68 g (64%) of ester (14) as a colourless oil; bp=130-140 0° C. (0.09 Torr); 1H NMR (300 MHz, CDCl3) δ 5.91 (m, 1H), 5.28 (m, 1H), 5.18 (m, 1H), 4.17 (s, 2H), 4.02 (m, 2H), 3.75 (s, 3H), 3.75-3.58 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 171.0, 134.8, 117.1, 72.3, 71.0, 70.8, 70.7, 69.5, 68.7, 51.8; IR (neat) 1754 cm−1; HRMS (ESI, m/z) calcd. for C10H19O5 (MH+) 219.1236. found 219.1227.