Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>O1CCCC1>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC2(CC1)OCCO2
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (8.19 g) in tetrahydrofuran (400 mL) was added dropwise a solution of EXAMPLE 341A (37.8 g) in tetrahydrofuran (75 mL). The mixture was then heated at reflux for 2 hours. The reaction mixture was cooled in an ice bath and quenched very slowly with water (8 mL). Then added sequentially were 4N sodium hydroxide (8 mL), ether (200 mL), water (24 mL), ether (500 mL) and anhydrous sodium sulfate (250 g). The resulting mixture was stirred rapidly for 2 hours and was filtered. The title compound was isolated by concentration of the filtrate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:12])([F:11])[CH2:9]I.[F:13][C:14]1[CH:42]=[CH:41][CH:40]=[CH:39][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]2[N:27]=[C:28]([OH:38])[C:29]3[C:34]([CH3:36])([CH3:35])[C:33](=[O:37])[NH:32][C:30]=3[N:31]=2)=[N:18]1>CN(C=O)C>[F:13][C:14]1[CH:42]=[CH:41][CH:40]=[CH:39][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]2[N:27]=[C:28]([O:38][CH2:9][C:8]([F:12])([F:11])[F:7])[C:29]3[C:34]([CH3:36])([CH3:35])[C:33](=[O:37])[NH:32][C:30]=3[N:31]=2)=[N:18]1
Reactant: FC(F)(F)CI
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(OCC(F)(F)F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
177 mg (0.54 mmol) of caesium carbonate and 114 mg (0.54 mmol) of 2,2,2-trifluoroethyl iodide were added to a suspension of 200 mg (0.5 mmol) of the compound from example 109 in DMF (1.97 ml) and it was stirred overnight at RT. Then it was heated in the microwave to 120° C. for 1 h. The reaction mixture was purified by preparative HPLC (Chromatorex C18, gradient of acetonitrile/0.01% aq. formic acid). Yield: 14.5 mg (6% of theor.).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1)[CH2:5]Br.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.O>C(#N)C>[CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1)[CH2:5][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CON=C(CBr)c1ncc(Cl)cc1Cl
Solvent: O
Solvent: CC#N
Product: CON=C(CNC1CC1)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To 700 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-methyloxime prepared in the same manner as in Steps 1 to 3 in Synthetic Example 2 in 10 ml of acetonitrile, 402 mg of cyclopropylamine in 5 ml of acetonitrile was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (40 ml×2, the resulting organic layers were combined, washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 3:7 to 5:5) as the eluent to obtain 450 mg of the desired product as a colorless resinous substance.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].[N+:32](C1C=C(Cl)C=CC=1O)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:4]([N+:32]([O-:34])=[O:33])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
To a solution of (2R, 5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester (1.0 g, 3.35 mmol) in butanone (35 ml) was added 2-nitro-4-chlorophenol (0.639 g, 3.69 mmol), potassium carbonate (0.925 g, 6.7 mmol) and potassium iodide (0.556 g, 3.35 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Chromatography on silica gel gave the title compound (1.35 g, 93% yield).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH:16]1[C:33]2[C:20](=[CH:21][C:22]3[C:31]([CH:32]=2)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=3)[CH:19]=[CH:18][CH:17]=1>ClC1C=CC=CC=1Cl>[CH:19]1[C:20]2[C:33](=[C:32]([CH:9]=[O:10])[C:31]3[C:22]([CH:21]=2)=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc2cc3cc4ccccc4cc3cc2c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=Cc1c2ccccc2cc2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a 3-necked RB flask equipped with overhead mechanical stirrer, condenser, addition funnel, N2 inlet line with bubbler was added n-methylformanilide (Aldrich 89.21 g, 0.66 mol, 81 mL) and o-dichlorobenzene (Aldrich, 200 mL). The mixture was cooled to 10° with an ice bath. Phosphorus oxychloride (Aldrich, 101.21 g, 0.66 mol, 60 mL) was then added dropwise to the solution not allowing the reaction temperature to rise above 10°. The reaction mixture was then allowed to warm to RT. Solid naphthacene (Cambridge Chemical, Inc., 50 g, 0.22 mol) was then added in five portions over 5 min. The reaction mixture was warmed slowly to 80° (the mixture turns from purple to an almost black color). The reaction was stirred at 80° for 12 h, cooled, poured into ice water (2 L) and stirred an additional 12 h at RT. The mixture was then filtered. The organic layer in the filtrate was dried (Na2SO4) and applied to a plug of SiO2 (500 g) and eluted first with PhCH3 followed by CH2Cl2. The appropriate fractions were combined and the solvent removed by rotary evaporation. Recrystallization (CH2Cl2 /EtOAc) gave 17.5 g (31.1% yield) of naphthacene-5-carbaldehyde, mp 163°-164° (Lit. 164°, N. P. Buu-Hoi et al., Recueil 76 674 (1957)), (C,H). The solid from the filtration of the crude reaction mixture was washed with a large volume of CH 3 OH (5×200 mL), dissolved in THF (4 L) and passed through a plug of SiO2 (500 g) using an additional 2 L of THF as eluting solvent. The solvent was reduced to a volume of 300 mL and then diluted to 800 mL with EtOAc. The solvent volume was reduced to 250 mL. After filtration and drying 10.90 g (17.4% yield) of naphthacene-5,11-dicarbaldehyde, mp 247°-250°, (C,H).
Reaction SMILES: [OH:1][C:2]1([CH3:40])[CH:26]=[C:25]2[C@:20]([CH3:38])([CH2:21][CH2:22][C@H:23]([O:27][Si](C(C)C)(C(C)C)C(C)C)[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:39])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.N#N>>[OH:27][C@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:38])[C:25](=[CH:26][C:2]([OH:1])([CH3:40])[C@@H:3]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:39])[C@H:4]3[CH2:5][CH2:6][C@@H:7]2[C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:24]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC1=CC3(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O)CC1=CC3(C)O
Yield: 60.4 %

Procedure:
A mixture of methyl 7-hydroxy-7-methyl-3β-triisopropylsilyloxychol-5-en-24-oate (6) (4.67 g, 8.22 mmoles) and tetrabutylammonium fluoride (1.0M in THF, 49 ml) was heated at 65° in a N2 atmosphere for 30 min. Most of the THF was removed in vacuo. The residue was dissolved in EtOAc (90 ml) and washed with H2O (two times) and saturated brine. The aqueous phases were back-extracted with EtOAc. The combined EtOAc extracts were dried (MgSO4). Evaporation in vacuo and flash chromatography on silica gel with 7% methanol-CH2Cl2 gave 2.08 g of 8 as a yellow-brown foam. NMR (CDCl3) indicated a mixture of 7-isomers: d 0.70 (two peaks, 18-Me); 3.66 (CO2Me); Further elution gave 0.50 g of the tertiary alcohol 7 as a mixture of 7-isomers. NMR (CDCl3): δ 0.70 (two peaks, 18-Me); 1.20 (CMe2OH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:18]=[CH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:37]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:18]=[CH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=1[CH3:32])[CH3:37])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a 0° C. solution of {4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-carbamic acid tert-butyl ester (1.9 g, 3.9 mmol) in DMF (15 mL) is added sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.7 mmol) portionwise. The mixture is stirred at 0° C. for 30 minutes. Iodomethane (0.83 g, 5.9 mmol) is added dropwise. The reaction mixture is then stirred at room temperature for 1.0 h. The reaction is quenched with the addition of saturated ammonium chloride (20 mL) at 0° C. The reaction mixture is partitioned between EtOAc (30 mL) and water (20 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound (1.85 g, 95%) as a foamy solid. LC-ES/MS m/e 526.0 (M+23).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([O-])=O>[Pd].C(O)C>[N:16]1[CH:17]=[CH:18][C:13]([C:9]2[N:8]([CH2:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:21]=[CH:20][CH:19]=3)[CH:12]=[CH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(Cn2ccnc2-c2ccncc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(Cn2ccnc2-c2ccncc2)c1
Reaction time: 4 h

Procedure:
Ethanol (20 mL) is added to 4-[1-(3-Nitro-benzyl)-1H-imidazol-2-yl]-pyridine (730 mg, 2.6 mmol) and 10% palladium on charcoal (100 mg) under an atmosphere of argon. The atmosphere is purged 3 times with H2 on a Parr shaker type hydrogenation apparatus, and the mixture is shaken for 4 h at 50 psi H2. The mixture is filtered through celite, and the filter pad is washed with DCM and MeOH (1:1). The solution was concentrated under reduced pressure to afford 3-(2-Pyridin-4-yl-imidazol-1-ylmethyl)-phenylamine as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[I:18]Cl.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[C:16]([I:18])=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: ClI
Reactant: Oc1cc2cnnc(-c3ccccc3F)n2n1
Solvent: CC(=O)O
Solvent: O
Product: Oc1nn2c(-c3ccccc3F)nncc2c1I
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
To a stirred mixture of 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.5014 g, 2.18 mmol) in glacial acetic acid (10 ml) was added dropwise a 1.0 M solution of iodine monochloride in glacial acetic acid (3.26 ml, 3.26 mmol) and the mixture was stirred at room temperature for a total of 1.25 h. Water (40 ml) was then added and the resulting solid was collected by filtration, washed with water, and dried under vacuum at 60° C. to yield 0.7345 g (95%) of the title compound as a pale brown solid; 1H NMR (360 MHz, d6 -DMSO) δ 7.42-7.49 (2H, m), 7.71 (1H, m), 7.79 (1H, m), 9.26 (1H, s), 12.48 (1H, s); MS (ES+) m/e 357 [MH]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=[O:20])=[CH:16][CH:17]=2)[C:12]([Br:21])=[N:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>CN(C=O)C>[Br:21][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)[N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[N:11]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(C=O)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Br)c2cc(CO)ccc21
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Sodium borohydride (395 mg; 10.4 mmol; 2.9 eq.) was added in one portion to a solution of tert-butyl-3-bromo-5-formyl-1H-indazole-1-carboxylate (1.20 g; 3.58 mmol; 1.0 eq.) in DMF (30 mL). The reaction mixture was stirred for 3 h then poured into HCl (0.1N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the tittle compound as a yellow solid (1.19 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J=8.7 Hz, 1H), 7.69-7.60 (m, 2H), 4.66 (s, 2H), 1.65 (s, 9H). HPLC (Condition A): Rt 3.65 min (purity 81.6%). MS (ESI+): 327.1, 329.1.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:12][CH3:13])[CH2:10][OH:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:11][CH2:10][C@@H:9]([NH:8][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC[C@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Triethylamine (0.94 ml, 6.74 mmol) was added to a solution of 400 mg (4.49 mmol) of (S)-2-aminobutan-1-ol in tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 10 min. 2-Nitrobenzenesulfonyl chloride (995.1 mg, 4.49 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 min. A saturated aqueous sodium hydrogencarbonate solution was added thereto to stop the reaction, and the reaction solution was then extracted with ethyl acetate, was dried over anhydrous sodium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 1.22 g (yield 99%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1Oc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A solution of 35.08 g of methyl 2-(4-methylphenoxy)benzoate, 25.7 g of N-bromosuccinimide, 0.57 g of azobisisobutyronitrile, and 1200 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 4.51 g of crude methyl 2-(4-bromomethylphenoxy)benzoate which was used in a subsequent reaction without further purification; NMR (200 MHz, CDCl3): δ 7.92 (d of d, 1H); 7.45 (t of d, 1H); 7.16 (m, 3H); 6.90 (m, 3H); 4.49 (s, 2H); 3.83 (s, 3H).
Reaction SMILES: [CH:1]1([C:8]([CH2:10]Br)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[C:23](=[S:25])[NH2:24])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>C(O)C>[CH:1]1([C:8]2[N:24]=[C:23](/[CH:22]=[CH:21]/[C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=3)[S:25][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)/C=C/c1cccc([N+](=O)[O-])c1
Reactant: O=C(CBr)C1CCCCCC1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Temperature: 0 °C
Yield: 62.7 %

Procedure:
A solution composed of 6.57 g of bromomethyl cycloheptyl ketone, 6.24 g of (E)-3-(3-nitrophenyl)-2-propenethioamide and 100 ml of ethyl alcohol was heated to reflux for 16 hr afterwhich it was diluted with 200 ml of ice water and extracted with methylene chloride. The combined extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and condensed in vacuo to yield 6.17 g of (E)-4-cycloheptyl-2-[2-(3-nitrophenyl)ethenyl]thiazole; m.p. 60° C. after crystallization from ethyl ether/hexane.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[C:6]([N+:12]([O-])=O)[C:5]=1[CH3:15])([O-])=O.N1CCOCC1>[Pt]>[NH2:1][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[C:6]([NH2:12])[C:5]=1[CH3:15]
Reactant: Cc1c([N+](=O)[O-])cc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1COCCN1
Product: Cc1c(N)cc(Cl)c(Cl)c1N

Procedure:
The catalytic hydrogenation of 2,6-dinitro-3,4-dichlorotoluene with platinum at 45° C. under a hydrogen-pressure of 10 bar in the presence of catalytic amounts of morpholine gives, for example, the 2,6-diamino-3,4-dichlorotoluene in high yields and high purity.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C([OH:18])(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:18])[CH:8]=[CH:9][CH:10]=1
Reactant: Clc1ccccc1Oc1cccnc1
Reactant: CC(C)O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2ccccc2Cl)c1

Procedure:
A solution of 74.3 g of 3-(2-chlorophenoxy)pyridine [Agr. Biol. Ghem., 34, 68 (1970)] in 75 ml of glacial acetic acid in three equal portions. The temperature is maintained at 35°-40° C. for 16 hours and 75 ml of isopropanol is added and the mixture is refluxed 1 hour. The mixture is concentrated at reduced pressure and the oil is dissolved in 500 ml of dichloromethane. The extract is washed with 25% sodium hydroxide solution, concentrated and distilled to yield 3-(2-chlorophenoxy)pyridine 1-oxide, bp 145°-160° C. at 0.15 mM, mp 60°-64° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][N:8]=2)[S:5][CH:6]=1>ClCCCl.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][N:8]=2)[CH:13]=[O:14])[S:5][CH:6]=1
Reactant: Cc1csc(-c2cc(CO)ccn2)n1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: Cc1csc(-c2cc(C=O)ccn2)n1
Temperature: 25 °C

Procedure:
A solution of (2-(4-methylthiazol-2-yl)pyridin-4-yl)methanol (750 mg; 3.64 mmol) in anh. DCE (40 ml) was treated with MnO2 (1.581 g; 18.20 mmol), and the resulting mixture was heated at reflux, under nitrogen, for 1.5 h. After cooling to rt, the resulting reaction mixture was filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 2-(4-methylthiazol-2-yl)isonicotinaldehyde as an off-white solid. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 205.04 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=O)=[C:4]([O:28][CH3:29])[CH:3]=1>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[C:26]=2[CH:27]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccc(F)cc2OC)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(OC)cc(F)cc32)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
A stirring mixture of title compound 92 (2 g, 5.06 mmol) in polyphosphoric acid (4.76 ml, 41.7 mmol) was heated at 130° C. for 3 h. The reaction mixture was cooled, diluted with dichloromethane and water and stirred overnight. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and solvent evaporated. The crude residue was purified via ISCO (0-25% Hex/EtOAc; 40 g silica gel column) to afford title compound 93 (125 mg, 6.5%) as a light yellow solid. LRMS (ESI): (calc) 377.11. (found) 378.4 (MH)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[N:29]#[C:30]Br>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]#[N:29])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(Methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step A, Example 11; 310 mg, 0.957 mmol) and potassium carbonate (489 mg, 3.54 mmol) were stirred in chloroform (15 mL). Cyanogen bromide (122 mg, 1.15 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (99:1, 1 L to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.71 (dd, J=0.5, 2.5 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.84 (dd, J=0.6, 8.7 Hz, 1H), 4.48 (t, J=7.2 Hz, 2H), 3.50-3.35 (m, 2H), 3.07 (s, 3H), 3.05-2.90 (m, 2H), 2.15-2.00 (m, 1H), 1.85-1.75 (m, 2H), 1.60-1.35 (m, 3H), 1.00-0.85 (m, 2H), 0.80-0.50 (m, 2H), −0.12 (q, J=5.0 Hz, 1H). MS (Multimode) m/z 339 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:19][CH2:20][CH2:21][Cl:22])([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C1Sc2cc(Cl)ccc2OCC1=O
Reactant: ClCCCBr
Product: COC(=O)C1(CCCCl)Sc2cc(Cl)ccc2OCC1=O

Procedure:
Methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate is treated with 1-bromo-3-chloropropane in the same manner as described in Reference Example 25 to give methyl 7-chloro-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:6]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=1)(=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccc(Cl)nc1

Procedure:
To 40 ml of a solution of 5.28 g of 6-chloronicotinoyl chloride in benzene, 16 g of aluminum chloride was added under ice-cooling and the resulting mixture was heated under reflux for six hours. After cooling, the reaction mixture was poured into a solution of ice/hydrochloric acid and extracted with ether. The organic phase was washed with water and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate and distilling off the solvent, 4.6 g of 3-benzoyl-6-chloropyridine was obtained. m.p.: 39°-40° C.