Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([Pb+3])=[C:31]([CH2:36][CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH2:36][CH3:37])[CH:30]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 45.7 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6 g, 38.96 mmol) and 4-dimethylaminopyridine (23.76 g, 194.75 mmol) are added to a mixture of chloroform (120 ml) and toluene (30 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (24.3 g, 42.85 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases separated. The aqueous phase is extracted with dichloromethane (2×50 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2-ethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (6 g).
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C@H:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:36])[N:29]([CH3:35])[CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:35][N:29]([CH2:30][C:31]([F:34])([F:32])[F:33])[C:28]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:22]([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:23]1)=[O:36]
Reactant: CN(CC(F)(F)F)C(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(F)(F)F)C(=O)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Yield: 52.4 %

Procedure:
A solution of racemic trans 3-[3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-1-methyl-1-(2,2,2-trifluoro-ethyl)-urea (80.0 mg, 150 μmol) and sodium hydroxide solution (1.5 mL, 1N) in methanol (1 mL) and THF (1 mL) was stirred at ambient temperature for 30 minutes. Dilute HCl was added and the mixture purified by Isolute® SCX-2 column (gradient: methanol to 2M NH3 in methanol solution). The residue obtained was purified further by trituration with DCM/diethyl ether to afford 30 mg (51%) of racemic trans 1-methyl-3-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-1-(2,2,2-trifluoro-ethyl)-urea as a white solid. LCMS (Method A, ESI): RT=3.40 min, m+H=382.10; 1H NMR (400 MHz, DMSO) δ: 12.36 (s, 1H), 9.00 (s, 1H), 7.61 (t, 1H), 7.00 (dd, 1H), 6.67 (d, 1H), 5.66 (m, 1H), 4.41 (m, 1H), 4.09 (q, 2H), 2.97 (s, 3H), 2.50 (m, 2H), 2.27 (m, 3H), 1.79 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([NH:29][C:30](=[O:33])[CH2:31]O)=[CH:27][CH:26]=1.O1CCCC1>C(O)(=O)C.CCCCCC>[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([NH:29][C:30](=[O:33])[CH2:31][O:18][CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:16])[CH3:17])=[CH:11][CH:10]=2)=[CH:27][CH:26]=1
Reactant: O=C(CO)Nc1ccc(Cl)cc1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: COC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(OCC(=O)Nc2ccc(Cl)cc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether, (8.0 g, 0.028 mole), p-chloroglycolanilide (5.23 g, 0.028 mole), 170 ml of tetrahydro-furan, 120 ml of n-hexane, and 4.5 ml of glacial acetic acid was refluxed for about 8.5 hours, replacing solvent as distillate was removed. Color was then discharged by the addition of 20 drops of tetramethylguanidine and the solution was filtered hot. Hexane was added to the filtrate, yielding a light green oil. The oil was removed and the hexane solution, on cooling, gave a light blue solid. The solid was filtered, washed with petroleum ether and dried. Recrystallization from 150 ml methylcyclohexane/40 ml acetone gave a yellow-white, gummy solid. This was recrystallized from VM&P naphtha to give a fine white powder, mp 137.5°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([C:16]([OH:18])=[O:17])=[CH:9][C:10]=1[S:11]2.OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:17][C:16]([C:8]1[CH:7]=[CH:6][C:5]2[S:4][C:3]3[C:12](=[CH:13][CH:14]=[CH:15][C:2]=3[Br:1])[S:11][C:10]=2[CH:9]=1)=[O:18]
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Temperature: 80 °C

Procedure:
To 6-bromo-thianthrene-2-carboxylic acid (9 g, 28 mmol) in methanol (180 ml) was slowly added conc. H2SO4 (5 ml). The milky white suspension was heated to 80° C. until all the solid had gone into solution (2 hrs). The suspension was concentrated in vacuo. Water (100 ml) was added and the organics were then extracted with dichloromethane (3×70 ml), dried over MgSO4 and evaporated in vacuo, yielding to a yellow solid. (4.48 g, 45%). 1HNMR (300 MHz, CDCl3): δH=3.94 (3H, s); 7.13 (1H, t), 7.44 (1H, dd), 7.54 (1H,dd) 7.61 (1H, d), 7.93 (1H, dd), 8.13 (1H, d).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[N+:17]([O-])=O)=O>C(O)(=O)C.[Fe]>[O:2]=[C:3]1[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=2[O:7][C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=2[NH:17]1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2C(=O)OC)s1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Temperature: 85 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a stirring solution of compound 118 (1.918 g, 5.69 mmol) in acetic acid was added iron (2.223 g, 39.8 mmol) and the reaction mixture was stirred at 85° C. for 1 h then at 100° C. for 1 h. The mixture was cooled to room temperature, poured into 150 mL of ice-cold water and the resulting white precipitate was filtered to afford title compound 119 (1.261 g, 81%) as a beige solid. LRMS (ESI): (calc) 275.03 (found) 276.2 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
A mixture of 4.50 g. of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine, 2.58 g. of acethydrazide and 100 ml. of n-butanol is heated at reflux temperature for 3 days. The solvent is removed and the residue dissolved in methylene chloride, passed through magnesol and the solid from the filtrate recrystallized from methylene chloride/hexane to afford the product as tan crystals, m.p. 199°-201° C.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[C:13]([CH:14]=O)=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[C:6](=[O:16])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:20])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2[nH]c1=O
Temperature: 23 °C

Procedure:
A solution of 5-2 (1.53 g, 6.88 mmol, 1 equiv), diethyl malonate (2.09 mL, 13.8 mmol, 2.00 equiv), and piperidine (0.340 mL, 3.44 mmol, 0.500 equiv) in ethanol (20 mL) was heated at reflux for 16 h. The reaction mixture was allowed to cool to 23° C. The white crystals which formed were filtered and washed with ethanol (20 mL) to give 2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (5-3). 1H NMR (400 MHz, CDCl3) δ 11.9 (br s, 1H), 8.85 (dd, 1H, J=4.8, 1.7 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=7.9, 1.6 Hz), 7.27 (dd, 1H, J=7.9, 4.8 Hz), 4.45 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][O:3]1.[CH3:25][NH:26][CH3:27]>CCO>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)[CH2:9][CH2:8]1)[C:2]([N:26]([CH3:27])[CH3:25])=[O:1]
Reactant: CNC
Reactant: O=C1OCCC1N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Solvent: CCO
Product: CN(C)C(=O)C(CCO)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.26 g (0.76 mmol) of (rac)-4-(2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (example 15C) was dissolved in 3 ml of EtOH and treated with 2.71 ml (15.19 mmol) of a solution of dimethylamine (5.6 M in EtOH). The reaction was stirred 20 h at RT, evaporated and re-evaporated with toluene to afford 0.31 g (quantitative) of the title compound as yellow oil. MS: 388.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 85%).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1(OC)C=CC=CC=1.C.[H][H]>[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: COc1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1 Part of nitroanthraquinone with a content of 97.0 percent of 1-nitroanthraquinone, 9 parts of anisole and 0.005 parts of catalyst (10 percent Pd on active charcoal) are heated to 130° in an autoclave with a capacity of 20 parts by volume and equipped with a rotary agitator. While heating, rinsing with nitrogen is effected and, on reaching the reaction temperature, hydrogen is passed through to provide a total pressure of 6.0 kp per cm2, at which the agitator is activated and hydrogenation effected until an amount of hydrogen corresponding to 264 parts by volume is taken up. The hydrogen is now followed by nitrogen and the catalyst separated, the filtrate cooled down to room temperature, when 1-aminoanthraquinone is formed in easily filtrable crystals. The crystallization product is separated, washed with a small quantity of cold benzene and dried at 100° and 20 mm of Hg. 0.83 Parts of a product containing 98.0 percent of 1-aminoanthraquinone are obtained, which corresponds to a yield of 95.1 percent of the theory. By concentrating the mother liquor, a further 0.05 parts of a product containing 71 percent of 1-aminoanthraquinone is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)(=[O:50])[CH:48]=[CH2:49]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([C:14]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:49]=[CH:48]/[C:47]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:50])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:24]
Reactant: C=CC(=O)N1CCOCC1
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(/C=C/C(=O)N4CCOCC4)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 51.2 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (584 mg, 1.5 mmol) in N,N-dimethylformamide (10 mL). To the solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (91 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), triethylamine (0.6 mL), and a solution of 4-acryloylmorpholine (254 mg 1.8 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness under reduced pressure. The resulting solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 345 mg of 2-ethyl-7-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp>260° C.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH:13]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOCC>[N:13]1([C:1]([O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:10])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. was added to methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15 mmol) and K2CO3 (6.68 g, 48.3 mmol) in THF:water (100 mL, 1:1). The reaction mixture was stirred at room temperature for 2 hours. Ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[OH-].[Na+]>CCOCC.O>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6]
Reactant: CSc1ccccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(methylthio)benzonitrile (29.8 g) in dry ether (150 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (1.16 g) in dry ether (360ml) under nitrogen. A thick gum formed which was dissolved by the addition of dry THF (100 ml). The mixture was stirred at room temperature for 2 hours. Water (12 ml) was then carefully added followed by a 15% aqueous solution of sodium hydroxide (36 ml) and more water (12 ml). The mixture was filtered, the filtrate washed with water, dried and evaporated in vacuo. The residue was distilled in vacuo to give a colourless oil. Yield=20.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:19]Br.O>C(O)(=O)C>[Br:19][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]#[N:13])[CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CCC#N)cc1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)cc(CCC#N)cc1Br
Reaction time: 8 h

Procedure:
62.8 g (358.4 mmol) of 3-(4-methoxy-5-methylphenyl)propanenitrile are dissolved in 390 mL of acetic acid. There are then added, all at once, 58.8 g (716.8 mmol/2 eq.) of sodium acetate and then, dropwise, 20.2 mL (394.2 mmol/1.1 eq.) of bromine, and stirring is carried out at ambient temperature overnight. The reaction mixture is then poured into 2 liters of water, and the aqueous phase is extracted 3 times with 500 mL of dichloromethane. The combined organic phases are washed successively with 500 mL of water, 500 mL of saturated aqueous sodium hydrogen carbonate solution and 500 mL of water, and are dried over magnesium sulphate. After concentration, the expected product is collected.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25](OC4C=CC([N+]([O-])=O)=CC=4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[NH2:39][CH:40]1[CH2:44][CH2:43][N:42]([C:25]([N:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)[CH2:14][CH:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]=3)[CH2:10]2)=[O:26])[CH2:41]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: NC1CCNC1
Agent: Cl
Product: NC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)C1

Procedure:
100 mg (0.20 mmol) of the compound from Example 184A and 95 mg (0.60 mmol) of 3-aminopyrrolidine dihydrochloride were reacted according to the General Method 6. Yield: 25 mg (27% of theory)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14]([CH2:21][OH:22])[C:15]([CH2:19][OH:20])=[CH:16][C:17]=1[F:18].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[F:11][C:12]1[CH:13]=[C:14]([CH:21]=[O:22])[C:15](=[CH:16][C:17]=1[F:18])[CH:19]=[O:20]
Reactant: OCc1cc(F)c(F)cc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cc(F)c(F)cc1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (4.5 ml, 8.8 mmol, 2.2 molar equivalents) cooled to −78° C. was added dropwise a solution of dimethylsulfoxyde (DMSO) (1.25 ml, 17.7 mmol, 4.4 molar equivalents) in DCM (5 ml). The solution was stirred at −78° C. for 5 minutes and 4,5-difluorobenzene-1,2-dimethanol (compound 21) (0.70 g, 4.0 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM/DMSO (1-2 ml) was added dropwise. The solution was stirred for 1 hour at −78° C. and triethylamine (15 ml) was slowly added at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (25 ml) was added to the reaction mixture and the aqueous layer extracted with DCM (3 times 30 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a yellow oil. Purification by column chromatography on silica gel (eluent, hexane:DCM 2:8) gave the title compound as a light yellow solid (0.58 g, 85%). 1H NMR (300.13 MHz, CDCl3) δ(ppm) 7.83 (t, J=9.00 Hz, 2H) 10.49 (s, 2H). 19F NMR (282.38 MHz, CDCl3) δ(ppm) −127.10 (s).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:18][C:17]=2[O:28][CH2:29][CH3:30])[CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][C:17]=2[O:28][CH2:29][CH3:30])[CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(/C=C/C(=O)OC)ccc1-c1cccc(NCC(=O)OC(C)(C)C)n1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(CCC(=O)OC)ccc1-c1cccc(NCC(=O)OC(C)(C)C)n1
Yield: 99.5 %

Procedure:
A solution of 1.0 g of methyl(E)-3-{4-[6-(tert-butoxycarbonylmethylamino)pyrid-2-yl]-3-ethoxyphenyl}acrylate in 10 mL of methanol is stirred for 3 hours at room temperature in the presence of 200 mg of 10% palladium-on-charcoal under a hydrogen atmosphere. After filtering off the palladium and evaporating off the solvents, 1.0 g of methyl 3-{4-[6-(tert-butoxycarbonylmethylamino)pyrid-2-yl]-3-ethoxyphenyl}propionate is obtained. Yield=100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:38][O:39][C:40](=[O:47])[C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43]Br>CN(C=O)C>[CH3:38][O:39][C:40](=[O:47])[C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@@H:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)C(C)(C)CCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 80 °C
Yield: 77 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.126 g, 0.242 mmol) was dissolved in 3 ml DMF at room temperature and K2CO3 (0.267 g, 1.94 mmol) was added. 4-Bromo-2,2-dimethyl-butyric acid methyl ester (0.202 g, 0.969 mmol, prepared according to the procedure from Tetrahedron 1994, 50(32), 9825-30) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford the (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-butyric acid methyl ester (0.105 g, 77%).