Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:28]1[C@@H:32]2[CH2:33][NH:34][CH2:35][C@@H:31]2[CH2:30][N:29]1C(OC(C)(C)C)=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:29]3[CH2:30][C@@H:31]4[C@@H:32]([CH2:33][NH:34][CH2:35]4)[CH2:28]3)=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3C[C@H]4CNC[C@H]4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (25 mg, 0.069 mmol) in N,N-dimethylformamide (1 mL) were added (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (30 mg, 0.14 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol) and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to yield Boc protected product as a white solid, which was dissolved in methylene chloride (3.0 mL) and trifluoroacetic acid (0.20 mL, 2.6 mmol) was added. The reaction mixture was stirred at rt overnight. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (100×21.2 mm C18 column, 20-60% MeCN/water[10 mM Et2NH]) to afford the product as a white foam.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].O.[CH:6]([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([CH2:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10]1)([CH3:8])[CH3:7]>CC(O)=O.CCOC(C)=O>[CH:6]([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16](=[N:1][OH:3])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])=[N:10]1)([CH3:8])[CH3:7]
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of sodium nitrite (1.725 g) of water (5.42 ml) was added in portions to a solution of 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (2.57 g) in a mixture of AcOH (2 ml) and EtOAc (8 ml) at 20-25° C. and the mixture was stirred at the same temperature for 8 hours. EtOAc was added to the mixture, washed with sat. aq. NaHCO3 solution and brine, dried over MgSO4 and concentrated under reduced pressure to give a solid. The solid was triturated with IPE and collected by filtration to give 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime as a solid (1.71 g), which was identical to the authentic sample (the product of Preparation 1) by melting point and IR, MS and NMR spectra.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1CC#N)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH2:23][C:24]#[N:25])[N:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:24]#[N:25])[N:16]=1
Reactant: COc1cc(OC)nc(CC#N)n1
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Product: COc1cc(OC)nc(C(C#N)c2ccccc2[N+](=O)[O-])n1

Procedure:
The compound of the general formula (II) can be produced, for example, as follows. A 2-nitrophenylacetonitrile derivative is reacted with a 2-halogeno- or alkylsulfonyl-4,6-dimethoxypyrimidine in the presence of a base, or a 2-halogeno-nitrobenzene derivative is reacted with 2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile in the presence of a base, to obtain 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile (IV). The compound (IV) is subjected to oxidative decyanation to obtain a compound of the general formula (V). The nitro group of the compound (V) is reduced to convert it into an amino group to obtain a compound of the general formula (VI). The carbonyl group of the compound (VI) is reduced to a hydroxymethyl group to obtain a compound of the general formula (II).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[NH:37]([C:38]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)Nc3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added phenyl isocyanate (0.2 g) under ice-cooling. The mixture is stirred at the same temperature for 30 minutes, and the temperature thereof is raised to room temperature and then the mixture is stirred overnight. The reaction solution is distilled off and the resulting residue is recrystallized from dioxane to give 5-anilinocarbonylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.65 g) as colorless prisms, m.p. 269-271° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C:16]2[C:17](=[O:32])[NH:18][N:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.N>O>[F:9][C:4]1[CH:3]=[C:2]([N:18]2[C:17](=[O:32])[C:16]([O:15][C:14]3[CH:33]=[CH:34][C:11]([F:10])=[CH:12][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH:20]=[N:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). mp 178-180° C. 1H NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 6.89-7.04 (m, 4H), 7.45-7.52 (m, 1H), 7.45-7.52 (m, 1H), 7.61 (dt, J=6 Hz, 3 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 473 (M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15F3N2O4S.0.5 H2O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H, 3.13; N, 5.62.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=C)=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:35]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:35])=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 0.08 mmol) in CH2Cl2 (15 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to move excess ozone. NaBH4 (12.2 mg, 0.32 mmol) was added to the mixture in portions at rt, and the mixture was stirred overnight at rt. The reaction was quenched by water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layer was combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(hydroxylmethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 25%). 1H NMR (CDCl3): 0.00 (s, 4H), 0.09 (s, 2H), 0.87 (s, 8H), 1.28 (s, 4H), 1.53 (d, 3H), 1.98 (d, 2H), 3.53 (m, 2H), 4.25 (m, 1H), 4.98 (m, 1H), 4.61 (m, 1H), 5.71 (m, 1H), 6.90 (m, 1H), 7.12-7.38 (m, 10H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>C(O)C.[C].[Pd]>[NH2:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cnccc1-n1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.9 %

Procedure:
4-(1-Imidazolyl)-3-nitropyridine (2.10 g, 11.0 mmol) was dissolved in 20 ml of ethanol. After the atmosphere was replaced with nitrogen, 0.25 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for 3 days. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane:methanol=8:1-6:1 (v/v)] to obtain 1.62 g of a light brown solid (yield: 91.6%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17]C1C=C(CC(O)=O)C=CC=1>>[F:17][C:3]1[CH:2]=[C:1]([CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccc2c(c1)CC(c1ccccc1)C2
Reactant: O=C(O)Cc1cccc(F)c1
Product: Oc1ccc2c(c1)CC(c1cccc(F)c1)C2

Procedure:
2-(3-Fluorophenyl)indan-5-ol was prepared as described for 2-phenylindan-5-ol in Example 25(a-e) using 5 g of 3-fluorophenylacetic acid. 1H-NMR (400 MHz, d6-DMSO): 9.09 (s, 1H), 7.37-7.29 (m, 1H), 7.14-7.7.09 (m, 2H), 7.02-6.98 (m, 2H), 6.64 (d, 1H, J 1.7 Hz), 6.55 (dd, 1H, J 2.3, 8.1 Hz), 3.63 (k, 1H, J 8.3 Hz), 3.24-3.12 (m, 2H), 2.94-2.79 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([O:22]CC)=[O:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C(O)C>[C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([OH:22])=[O:21])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Temperature: 0 °C
Yield: 88.6 %

Procedure:
1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester (3,2 g) is heated with 1% KOH solution in ethanol (80 ml) under reflux for 30 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HCl. The precipitate is filtered, washed with water and dried in vacuo at 50° C. to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-carboxylic acid (2.6 g) which is reacted with thionyl chloride (0.9 ml) in dioxane (50 ml) under reflux for 2 hours. After cooling, the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-carbonyl chloride as a crystalline residue. The crude product is dissolved in anhydrous dioxane (35 ml) and reacted for 1 hour under stirring at room temperature with the carbanion obtained by treatment of N-cyanoacetylglycine, methyl ester (1.44 ng) with 50% sodium hydride (0.54 g) in anhydrous dimethylformamide/dioxane 1:1 (30 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 2 with N HCl. The precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with N HCl and then with water until neutral. Evaporation to dryness yields a residue which is purified over a Flash column using chloroform/methanol/30% NH4OH 80:20:0.5 as eluent. Final treatment with acetone of the purified fractions gives 1.65 g of N-[2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxopropanoyl]-glycine,methyl ester, m.p. 208°-210° C., NMR (CDCl3) δppm: 3.81(s) (3H, --COOCH3), 4.18 (d) (2H, --CONHCH2 --), 4.21(s) (2H, --S--CH2 --), 6.82(t) (1H, --CONHCH2), 6.85-7.7 (m) (9H, phenyl protons), 16.32(s) (1H, --OH).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][N:10]([CH3:13])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1.[C:16](OCC)(=[O:18])C>[Pd]>[CH3:16][O:18][CH:8]1[C:7]2[CH:15]=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]1=[O:14]
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CC(=O)N(C)C=C2
Agent: [Pd]
Product: COC1C(=O)N(C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
Weigh out 5% Pd on carbon (100 g) to a suitable container and wet the catalyst with ethyl acetate (2 L) while maintaining a nitrogen blanket. Charge the catalyst slurry to a 10-gallon autoclave and rinse the container with ethyl acetate (1 L) while maintaining a nitrogen purge. Add 8-methoxy-3-methyl-1,3-dihydrobenzo[d]azepin-2-one (920 g, 4.5 mol) to the autoclave and rinse with ethyl acetate (4 L). Purge the autoclave with nitrogen, seal the autoclave and pressurize with hydrogen to 50 psi while stirring at 800 rpm and maintaining the reaction temperature between 20-30° C. The reaction is determined to be complete by 1H NMR after 5 hours. Filter the autoclave contents over hyflo and rinse with ethyl acetate, then concentrate the filtrate to obtain the product methoxy-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one as an off-white solid (868 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)n2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccc(Cl)n3)n2)CN1

Procedure:
75 mg (0.21 mmol) of the compound of Example 21A is reacted analogously to the synthesis of the compound of Example 1 with 29 mg (0.23 mmol) of 4-imidazolinone-hydrochloride. 44 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9](/[CH:16]=[C:23](/[C:22]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH3:18])[CH:21]=2)\[C:24]#[N:25])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Product: COc1ccc(/C(C#N)=C/c2c3ccccc3c(Cl)c3ccccc23)cc1OC
Yield: 56.1 %

Procedure:
10-Chloro-9-anthraldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (368 mg) through Method A (production step 2), to thereby yield the target product (yield: 466 mg, 56%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.C(O)(=O)C.C(OCC)(=O)C>C1COCC1.O.CO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)C1CCN(c2ccc(F)cn2)CC1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ccc(F)cn2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A mixture of 4 g (16 mmol) 5′-Fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester and 0.832 g (20 mmol) LiOH.H2O in 50 mL THF, 50 mL water and 5 mL methanol was stirred for 2 h at 20° C. Acetic acid was added to pH 6 and water and ethyl acetate. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 3.1 g (87%) of the title compound as off-white solid. MS m/e: 223.1 [M−H].
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C(S(O)(=O)=O)=[CH:4][CH:3]=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13].C(OC1C=CC(N)=C(O)C=1)(=O)C.C(CC(=O)C)(=O)C>>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:7]([CH3:6])=[CH:2][C:3]([CH3:4])=[N:23]2)=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1ccc(NN)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)Oc1ccc(N)c(O)c1
Solvent: CC(=O)CC(C)=O
Product: CC(=O)Oc1ccc(-n2nc(C)cc2C)c(O)c1
Yield: 52.8 %

Procedure:
330 mg of the title compound was prepared in a manner similar to Example 54b) by using 4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate (0.9 g), which was prepared from 4-amino-3-hydroxyphenyl acetate (1.0 g) in a manner similar to Example 54a), and acetylacetone (0.9 g).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:20]([N:22](CC)CC)C.CN>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:22][CH3:20])=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: CCc1nc(Br)sc1C(=O)NC(C#N)c1cccs1
Agent: CN
Solvent: C1CCOC1
Product: CCc1nc(NC)sc1C(=O)NC(C#N)c1cccs1
Yield: 89 %

Procedure:
1.0g of 2-bromo-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.40ml of triethylamine and 0.58ml of methylamine were added to 10ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 4 hours and then treated according to the same procedure as EXAMPLE 10 to obtain 0.77g (Yield 89%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:19]1[CH2:29][CH2:28][C@H:27]([OH:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20]1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:29][CH2:28][C:27](=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20]1
Reactant: O[C@H]1CC[C@H](c2cccc(F)c2F)Cc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCC(c2cccc(F)c2F)Cc2cccnc21
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.91 mL, 11 mmol) in dichloromethane (15 mL) at −65° C. was added DMSO (0.94 mL, 13 mmol), and the mixture was stirred for 30 min. A solution of racemic trans 6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (prepared according to the procedures described by Leahy, D. K et al Org. Lett. 2012, 14, 4938-4941, 365 mg, 1.33 mmol) in dichloromethane (3 mL) was added drop wise and the resulting solution was stirred at −65° C. for 30 min. Triethylamine (2.55 mL, 18.6 mmol) was added and the reaction mixture was gradually warmed to 23° C. over a period of 4 h, and then partitioned between water and dichloromethane. The organic layer was washed with water (3×), brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 35% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=274.2 (M+1).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: BrCc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: O=C1CCC2N1CC(=O)N2Cc1ccccc1
Yield: 86.9 %

Procedure:
A solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994), BEMP (2 ml, 7 mmol) and benzylbromide (0.6 ml, 5 mmol) in CH3CN (20 ml) was refluxed for 1 hour. The reaction mixture was concentrated to dryness; the residue was then re-dissolved in ethyl acetate and washed with a saturated solution of NaCl, dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by flash chromatography over silica gel (CH2Cl2/MeOH/NH4OH 95/5/0.5) to afford 0.7 g of the title compound as yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18].[CH3:19]O>>[ClH:18].[CH3:19][O:16][C:14]([C:11]1([CH3:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(C)CCNCC1
Reaction time: 18 h

Procedure:
To a stirred solution of 4-methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.10 mmol) in MeOH (2 mL) is added HCl (5 ml, 4 M in dioxane). After 18 h, the mixture is evaporated to dryness, the residue is dissolved in MeOH (3 mL), and the stirred solution is treated with Et2O (45 ml). The resulting solid is filtered and dried to give the title compound.
Reaction SMILES: Cl.N([O-])=O.[Na+].[Cl:6][C:7]1[C:15]([N:16]=NC2C=CC(OC)=CC=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[ClH:6].[NH2:16][C:15]1[C:7]([Cl:6])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: COc1ccc(N=Nc2c(Cl)nn3ccccc23)cc1
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: Nc1c(Cl)nn2ccccc12
Reaction time: 0.5 h

Procedure:
2-Aminopyrazolo[1,4-a]pyridine (see Chem. Parm. Bull., 21, 2146/1973) is reacted with p-methoxybenzene diazonium salt analogously to Example 13.2. 0.53 g of the 3-azo compound obtained is suspended in 10 ml. 6N hydrochloric acid and mixed at +5° C., while stirring, with a solution of 104 mg. sodium nitrite in 0.2 ml. water. After 30 minutes, a cold solution of 198 mg. cuprous chloride in 6 ml. 6N hydrochloric acid is added thereto and the reaction mixture is stirred for 40 hours at ambient temperature. The mixture is mixed with water and extracted three or four times with ethyl acetate. After purification of the crude product by chromatography over silica gel (elution agent: ethyl acetate/ligroin 1:1 v/v), there are obtained 320 mg. of 2-chloro-3-(p-methoxyphenylazo)pyrazolo[1,5-a]pyridine (Rf =0.65; silica gel, ethyl acetate/ligroin 1:1 v/v) which is reduced with sodium dithionite analogously to Example 10.3. There is obtained the title compound; m.p. 249°-251° C. (decomp.). Rf =0.2 (silica gel, ethyl acetate/ligroin 1:1 v/v).