Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>C(Cl)Cl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:21][O:22][CH3:23])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(OC)cc1C=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (10 g, 67.5 mmol) and diisopropylethylamine (14 mL, 80 mmol) in CH2Cl2 (100 mL) was added chloromethyl methyl ether (6.1 mL, 80 mmol) at 0° C., and the mixture was stirred for 15 hours at room temperature. Then, water was added to the solution, the aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layer was washed with saturated aqueous NaCl (100 mL×2), water (100 mL×1), dried over MgSO4, and evaporated to afford the objective compound as a brown oil (11.76 g, 91%), which was used for next reaction without further purification: 1H-NMR (400 MHz, CDCl3) δ3.52 (s, 3H), 3.81 (s, 3H), 5.24 (s, 2H), 7.12 (dd, 1H, J=9.6, 3.2 Hz), 7.18(d, 1H, J=9.6 Hz), 7.32(d, 1H, J=3.2 Hz), 10.47 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](I)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)(=O)C>[Br:22][C:23]1[CH:28]=[C:27]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[N:3]=3)[NH:8][CH:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cnc2[nH]cc(-c3cccc(Br)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50 ml round bottom flask was charged under nitrogen with 2-chloro-7-iodo-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (6) (950 mg, 2.2 mmol), 3-bromophenyl boronic acid (440 mg, 2.2 mmol), tetrakis-triphenylphosphine palladium (50 mg, 0.04 mmol), 2M aqueous potassium carbonate (2.2 ml, 4.4 mmol) in a toluene/ethanol mixture (15/3 ml) under nitrogen. The reaction mixture was refluxed for 18 h, then allowed to cool to room temperature. The solution was diluted with ethyl acetate (˜70 ml). The organic was washed with brine, dried over magnesium sulfate and concentrated in vacuo, The residue was triturated in dichloromethane/methanol. A pale yellow solid was removed by filtration (300 mg). The residue was taken up in a tetrahydrofuran/methanol/1M NaOH mixture (4/1/1 ml) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in methanol. A solid was filtered off as the title compound (10 mg, 1%). 1H NMR (DMSO-d6): 7.35-7.45 (2H, m), 8.10-8.15 (1H, d), 8.35 (1H, s), 8.4 (1H, s), 8.6 (1H, s). MS (ES+): 310, 312.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][CH:12]([CH3:14])[CH3:13])[CH2:8]2.[CH3:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27](O)=[O:28])[CH:18]=[N:17]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:27]([C:19]1[CH:18]=[N:17][N:16]([CH3:15])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH2:8]2
Reactant: Cn1ncc(C(=O)O)c1-c1ccccc1
Reactant: CC(C)NC1C2CC3CC(C2)CC1C3
Product: CC(C)N(C(=O)c1cnn(C)c1-c1ccccc1)C1C2CC3CC(C2)CC1C3

Procedure:
Methyl-5-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-yl-isopropyl-amide is prepared from adamantan-2-yl-isopropyl-amine (of intermediate 3) and 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid (Maybridge plc, Cornwall, UK) according to general procedure C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15](=[O:28])[N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>CO>[O:28]=[C:15]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Reaction time: 22 h

Procedure:
Trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-carbamic acid tert-butyl ester (18.1 g, 0.045 mol) was taken up in MeOH (275 mL) and treated with 4 M HCl in dioxane (56 mL, 0.224 mol) and allowed to stand 22 hours. Concentration to dryness yielded a solid which was treated with 2N NaOH (175 mL) and extracted with CH2Cl2. The extracts were washed with water, brine, and dried (Na2SO4). After evaporation of the solvent, the residue was crystallized in Et2O yielding trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine as a white solid, 11.2 g (83%); mp 90-93° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[C:24]1([C:30]2[CH:31]=[C:32]3[N:37]([C:38]=2C2C=CC=CC=2)[CH:36]=[CH:35][CH:34]=[CH:33]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[C:49](=O)[CH3:50])(=O)C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:38]3[N:37]4[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]4)=[C:31]([C:50]4[CH:49]=[CH:6][CH:5]=[CH:4][CH:23]=4)[C:30]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20](=[O:22])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-c2cc3ccccn3c2-c2ccccc2)cc1
Product: CCn1c(C)c(C2(c3c(-c4ccccc4)c(-c4ccccc4)c4ccccn34)OC(=O)c3ccccc32)c2ccccc21

Procedure:
A mixture of 3.06 grams of (1-ethyl-2-methylindol-3-yl) (2-carboxyphenyl)ketone, 2.7 grams of 2,3-diphenylindolizine and 10 ml. of acetic anhydride was heated at about 50° C. for 107 minutes. The reaction mixture was cooled and filtered and the obtained product was recrystallized from a toluene-heptane mixture. The 3.3 grams of product were recrystallized from a toluene-heptane mixture to a constant melting point of 227°-227.5° C. A chloroform solution of the product when applied to silica gel produced a blue color.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:32]1C=CC=CC=1.N>C(#N)C>[NH2:32][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 10 g, 44 mmol), di-tert-butyl dicarbonate (CAN:24424-99-5, 14.28 g, 66 mmol) and pyridine (2.4 mL) in acetonitrile (200 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. During removal of most of the solvent under reduced pressure the product precipitated and the solid was filtered off and washed with acetonitrile (20 mL). The solid was dried under reduced pressure to give the title compound (7.73 g, 78%) as white solid; MS (EI): m/e 251.2 [M+Na]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCOCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH:34]1[C:39]([CH:40]=O)=[CH:38][C:37]2[O:42][CH2:43][O:44][C:36]=2[CH:35]=1>CCCCCC>[O:44]1[C:36]2[CH:35]=[CH:34][C:39]([CH:40]=[C:2]([CH3:3])[CH3:1])=[CH:38][C:37]=2[O:42][CH2:43]1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)=Cc1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
62.5 ml of a 1.6M solution of butyllithium in hexane was added to 500 ml of anhydrous ether. 38.5 g of isopropyltriphenylphosphonium bromide was added thereto in a nitrogen gas stream and the mixture was stirred for 4 h. 18 g of piperonal was added to the reaction mixture and the resulting mixture was stirred for 5.5 h and then filtered. The filtrate was washed with 1 l of ether, concentrated under reduced pressure and purified according to silica gel column chromatography (hexane/ethyl acetate=10:1) to obtain 13.1 g of the intended compound in the form of a colorless oil.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:26][N:24]([CH2:23][C:22]([NH:21][NH:20][C:18]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])=[O:27])[CH3:25]
Reactant: [H][H]
Reactant: CN(C)CC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 87.7 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-[(dimethylamino)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 241 (0.15 g, 0.40 mml) in methanol (20 mL) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite and the filtrate was evaporated to give (2R,5S)-N′-[(dimethylamino)acetyl]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 242 (0.10 g, 88%) as a white foam.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].BrC1C=CC=CC=1[C@@H]([N:26]=[C:27]=[O:28])C.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2([CH2:5][C:6]([CH3:8])=[CH2:7])[O:9][C:27](=[O:28])[NH:26][CH2:2][CH2:3]2)=[CH:11][CH:12]=1
Reactant: C=C(C)CC(O)(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N=C=O)c1ccccc1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)CC1(c2ccc(F)cc2)CCNC(=O)O1
Yield: 65.7 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (3.15 g, 13 mmol), (S)-(−)-1-(-bromophenyl)ethyl isocyanate (3.5 g, 16 mmol), and DBU (8 g, 33 mmol) in THF (80 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (3 x). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column to give (R)-3-(S)-1-(4-bromophenyl)-ethyl)-6-(4-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one (2.13 g, yield: 38%).
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>O>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:2]2[C:3]([N:7]3[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]3)=[N:4][S:5][N:6]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCN(c2nsnc2Cl)CC1
Reactant: OCc1ccncc1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid (7.99 g, 32 mmol), pyridin-4-yl-methanol (7.39 g, 68 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (100 mL, 100 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with H2O (500 mL) and washed with EtOAc (3×). The aqueous phase is concentrated to ˜250 mL and acidified to pH 5-6 with conc'd HCl. The resulting solids are filtered, washed with H2O and dried under high vacuum to give 6.04 g (59%) of 1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid. 1H NMR (DMSO-d6) 8.57 (d, 2H), 7.41 (d, 2H), 5.51 (s, 2H), 4.03 (m, 2H), 3.00 (m, 2H), 2.46 (m, 1H), 1.91 (m, 2H), 1.63 (m, 2H) ppm. LC-MS (M−)=319.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
4-Bromobenzene-1-sulfonyl chloride (2.56 g, 10 mmol) in anhydrous CH2Cl2 (10 mL) was added to a mixture of 1-methylpiperazine (2.0 g, 20 mmol), pyridine (2.37 g, 30 mmol) and anhydrous CH2Cl2 (10 mL) at 0° C. The mixture was stirred at room temperature for 16 h, concentrated, recrystallised, and dried over P2O5 to yield the sub-title compound (2.27 g, 71%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[NH:11][C:10](=O)[NH:9][C:6]2=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:17])=O>[Cl-].C[N+](C)(C)C>[Cl:17][C:10]1[NH:9][C:6]2=[N:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[C:5]2[N:11]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: FC(F)(F)c1cnc2[nH]c(Cl)nc2c1

Procedure:
Heat a solution of 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one. (0.6 g, 2.95 mmol) and tetramethylammonium chloride (0.3 g) to 110° C. in phosphorus oxychloride (10 mL) for 10 hours. After cooling, remove the excess POCl3 in vacuo, and then neutralize with saturated NaHCO3, extract with EtOAc. Dry over Na2SO4, concentrate under vacuum to obtain 2-chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine. D. 1′-(6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin-3-one
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][C:33]1[C:34]([C:49]2[S:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([NH2:60])=[O:59])[C:51]=3[CH:50]=2)=[N:35][C:36]([NH:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:37][CH:38]=1>>[ClH:3].[ClH:1].[CH3:32][C:33]1[C:34]([C:49]2[S:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([NH2:60])=[O:59])[C:51]=3[CH:50]=2)=[N:35][C:36]([NH:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([CH3:4])[CH2:45][CH2:44]2)=[N:37][CH:38]=1
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(N)=O)cccc2s1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2c(C(N)=O)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide and isolated as a yellow solid. ES+(m/z) 424 [M(free base)+H].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H][H].[CH3:13][S:14]([OH:17])(=[O:16])=[O:15]>[Pd].C(O)(C)C>[CH3:13][S:14]([O-:17])(=[O:16])=[O:15].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH3+:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)O
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CS(=O)(=O)[O-]
Product: N#Cc1ccc(C[NH3+])cc1
Yield: 77.8 %

Procedure:
1,4-Dicyanobenzene (2.0 g; 15.6 mmol) and palladium on activated carbon (1.0 mol % Pd/1,4-dicyanobenzene) were suspended in iso-propanol (30 mL) at 50° C. Hydrogen was continuously added at a pressure of 6 atm. When the desired conversion was obtained (2.5 h), the hydrogen was replaced by nitrogen and the solid material (Pd/C and unreacted 1,4-dicyanobenzene) was filtered off. Methanesulphonic acid (1.5 g; 15.6 mmol) was added to the clear solution. The crystals which formed were centrifuged, washed with a small amount iso-propanol and dried to yield 2.77 g (79%) of 4-cyanobenzylammonium methanesulphonate with a HPLC purity of 91.2 ae %.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:31](=[O:32])[C:13]3=[C:14]([C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)[NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1.C(O)(=O)C>C(O)C.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:31](=[O:32])[C:13]3=[C:14]([C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)[NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(-c4ccc([N+](=O)[O-])cc4)c-3c2=O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(-c4ccc(N)cc4)c-3c2=O)cc1
Yield: 82.6 %

Procedure:
4-[4-(4-Nitro-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoic acid methyl ester (2.6 g, 5.9 mmol) and Pd/C (100 mg, 10%) were suspended in ethanol (150 mL) and acetic acid (6 mL) and stirred under hydrogen for 24 h. The resulting yellow-orange suspension was diluted with DMF (50 mL) and filtered. The solvent was removed in vacuo to leave a residue which was washed with methanol to give 4-[4-(4-amino-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoic acid methyl ester (2.0 g, 82%) as a pale orange solid, LCMS m/z 411.39 [M+H]+ @ RT 1.27 min, 79% purity.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]#N)[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-:20].[K+].Cl.[OH-:23].[Na+]>O>[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]([OH:23])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: [OH-]
Reactant: CC(=O)Nc1cccc(-c2ccc(C#N)c(=O)[nH]2)c1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1

Procedure:
A mixture of 92.5 g (0.37 mol) of 6-(3-acetylaminophenyl)-1,2-dihydro-2-oxonicotinonitrile, 185 g of potassium hydroxide, and 740 ml of water is heated at 105° for 30 hrs. The cooled reaction mixture is poured into 285 ml of concentrated hydrochloric acid and ice. The pH of the suspension is adjusted to 5.0 with aqueous sodium hydroxide solution and the solid filtered, washed with water, and dried to give 81.2 g of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid. ##EQU49##
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]=3[O:14][C:13]=2[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=[O:31])C1.O>CO>[C:1]1([CH2:7][CH2:8][S:9]([CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]=3[O:14][C:13]=2[CH3:27])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc2c(CCSCCc3ccccc3)c(C)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Product: COC(=O)COc1cccc2c(CCS(=O)CCc3ccccc3)c(C)oc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Methyl (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate (340 mg) was dissolved in methanol (15 ml) and the obtained solution was cooled to −10° C. To this solution, NBS (190 mg) was added for 5 minutes and the resulting mixture was stirred at −10° C. for 30 minutes. This reaction solution was poured into water layer (100 ml) and the resultant was extracted twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: dichloromethane/ethyl acetate=2/1) using silica gel to obtain the desired compound (225 mg, yield: 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C(C)C)cc1OC
Reaction time: 3 h
Yield: 75.7 %

Procedure:
1.81 g of 4-amino-2-methoxy-benzoic acid methyl ester and 1.4 g of triethylamine were dissolved in 20 ml of dichloromethane. 1.23 g of isobutyryl chloride in 5 ml of dichloromethane was added dropwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 3 hours. The reaction mixture was washed with water, dried and the solvents were evaporated to yield 1.9 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[NH:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19]CC)=O)=[C:4]([F:24])[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>CN(C)C=O.C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:17](=[O:19])[CH:16]=[C:15]([CH3:22])[N:14]([CH3:31])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)/C=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C
Reaction time: 1 h

Procedure:
A solution of 9.00 g of ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-crotonate in 100 ml of anhydrous dimethylformamide is added dropwise at room temperature while stirring to a solution of 1.10 g of a 55% sodium hydride dispersion in 100 ml of isopropanol/dimethylformamide (1:1) and stirred for 1 hour. The reaction mixture is subsequently treated with 4.70 g of dimethYl sulphate and stirred at room temperature for 2 hours. The solvent is largely distilled off under reduced pressure and the residue is poured into 500 ml of water and extracted twice with 200 ml of ethyl acetate each time. The organic phases are washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6 -dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 149°-151° C.