Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([N:9]1C[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16])=[O:8])([O-:3])=[O:2].C1(=O)NCCCC1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C1CCCCCN1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
Synthesized as for N-(3,5-dinitrobenzoyl)caprolactam (Example XIX) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH:28]1([C:31](Cl)=O)[CH2:30][CH2:29]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:31]([CH:28]4[CH2:30][CH2:29]4)[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: O=C(Cl)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2noc(C3CC3)n2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and cyclopropanecarbonyl chloride following a procedure analogous to that described in Example 47. LC (method 2): tR=1.20 min; Mass spectrum (ESI+): m/z=420 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:32]3[CH2:33][CH2:34][CH:29]([NH2:28])[CH2:30][CH2:31]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 66.4 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol) obtained in Step 6 of Example 1, 4-(tert-butoxycarbonylamino)piperidine (538 mg, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (0.420 mL, 3.82 mmol) in a similar manner to Example 5, was dissolved in methanol (10.0 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (5.0 mL), followed by heating under reflux at 60° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure, the residue was extracted after adding with a saturated aqueous potassium carbonate solution and ethyl acetate. The crude product was crystallized from ethyl acetate to obtain Compound 64 (435 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]1[S:24][C:7]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Cl)c(C(Cl)=Nc2ccnc(Cl)c2F)c(Cl)c1
Reactant: NC(N)=S
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzimidoyl chloride (454 mg, 1.25 mmol), thiourea (380 mg, 5.0 mmol) and pyridine (325 μL, 4.0 mmol) in anhydrous isopropanol (4 mL) was heated under reflux, under nitrogen, for 16 hours. Triethylamine (1.05 mL, 7.5 mmol) was added and the resultant mixture was heated under reflux for a further 6.5 hours. The mixture was cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue was partitioned between DCM (15 mL) and water (15 mL). The aqueous phase was extracted with DCM (2×10 mL) and the combined organic extract was dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-20% EtOAc in DCM. The resultant solid was triturated with cyclohexane and dried under reduced pressure to give the desired compound as a white solid (275 mg, 65% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=5.6 Hz, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.79 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[N:26]=[C:25]([NH2:36])[N:24]=1)[CH2:19][NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>C(#N)C>[NH2:36][C:25]1[N:24]=[C:23]([C:22]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:19]3)=[CH:14][C:13]=2[F:12])[CH:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[N:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CCN(c2cc(-c3cc4c(cc3F)CCNC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)Nc3ccc(Cl)cc3)C4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
1-Chloro-4-isocyanatobenzene (4.1 mg, 0.026 mmol) was added to a mixture of 4-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (15 uL, 0.11 mmol) in acetonitrile (0.3 mL). After 30 min., the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=496.1/498.1.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CC(C)C[C@H](N[C:40]([C@@H:42]1[O:44][C@H:43]1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])C(N1CCN(C2C=CC=CN=2)CC1)=O>>[CH3:5][CH:4]([CH3:6])[CH2:3][C@H:2]([NH:1][C:40]([C@@H:42]1[O:44][C@H:43]1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(c2ccccn2)CC1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(c2ncccn2)CC1
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(c2ncccn2)CC1
Yield: 92.1 %

Procedure:
Monoethyl trans-epoxy succinate (3.52 g) and 1-L-leucyl-4-(2-pyrimidinyl)piperazine (6.10 g) were condensed in the same manner as employed in the preparation of ethyl trans-3-[(s)-3-methyl-1-{4-(2-pyridyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate to yield 8.50 g of ethyl trans-3-[(s)-3-methyl-1-{4-(2-pyrimidinyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate (yield: 92.1%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Mg]C.C([Li])CCC.[CH3:20][S:21]SC>C1COCC1>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([S:21][CH3:20])[CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: CSSC
Agent: C[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(F)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
A solution of 2-bromo-4-fluorobenzoic acid (15 g, 68.5 mmol, Aldrich) in THF (150 mL) under Argon at 0 degrees C. was treated with chloro(methyl)magnesium (5.64 g, 75.34 mmol, 2.94 M in THF) over 5 minutes. The temperature during addition was maintained below 10 degrees C. The resulting solution was cooled to −78 degrees C. and n-butyllithium (9.65 g, 150.7 mmol, 2.5M in hexanes) was added over 10 minutes. The reaction was kept below −65 degrees C. during the addition. The reaction was stirred at −78 degrees C. for 50 minutes. A solution of (methyldithio)methane (38.71 g, 410.9 mmol) in THF (20 mL), precooled to −78 degrees C., was added by cannula. The reaction was stirred for 10 minutes, warmed to zero degrees C. and stirred at zero degrees C. for 2 hours until a solid began to precipitate. The reaction was allowed to warm to 25 degrees C. The material was filtered and the solid partitioned between ethyl acetate (400 mL) and water (400 mL). The water layer was acidified with HCl to pH of less than 1 and then extracted with ethyl acetate (4×500 mL). The organic was dried over Na2SO4, filtered, and reduced to a small volume in vacuo to produce crystals. The crystals were filtered and dried in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:4][C:3]=1[F:16].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:4][C:3]=1[F:16]
Reactant: O=C(O)C1CC(O)(c2ccc(Br)c(F)c2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC(c2ccc(Br)c(F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
Into a 1000-mL round-bottom flask was placed a solution of 3-(4-bromo-3-fluorophenyl)-3-hydroxycyclobutane-1-carboxylic acid (50 g, 172.95 mmol, 1.00 equiv) in trifluoroacetic acid (500 mL) and triethylsilane (40.1 g, 344.87 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The resulting solution was diluted with 200 mL of EA and washed with 2×200 mL of saturated aqueous sodium carbonate. The aqueous layers were combined and extracted with 3×500 mL of EA. The pH value of the aqueous layer was adjusted to 4 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×500 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of water and 1)(1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 35 g (crude) of 3-(4-bromo-3-fluorophenyl)cyclobutane-1-carboxylic acid as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.S(=O)(=O)(O)[OH:22]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: OO
Solvent: CO
Product: COc1ccc(O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.), stirred solution of 3-benzyloxy-4-methoxybenzaldehyde (10 g) in MeOH (100 mL) was added hydrogen peroxide (5.5 mL of 30% aqueous) dropwise. After having been warmed to RT, concentrated sulfuric acid (1 mL) was added and the resulting solution was allowed to stir for 1.5 h. The reaction mixture was partitioned between ethyl ether/saturated aqueous sodium bicarbonate, another organic layer was dried over sodium sulfate and concentrated in vacuo to afford an oil. Flash chromatography (20% ethyl acetate/hexanes) afforded 3-benzyloxy-4-methoxyphenol (5.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[NH:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CN(C)CCN
Solvent: O
Product: CC(C)n1nc(-c2nc(NCCN(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and N,N-dimethyl-1,2-ethanediamine (0.127 ml) in 1,2-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), the mixture was extracted with CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel [Chromatorex® NH] eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a syrup. The syrup was crystallized from a mixture of acetone and n-hexane to give 6-(5-amino-6-{[2-(dimethylamino)ethyl]amino}-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (36 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].[OH-].[Na+]>>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:5]([CH3:17])([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3-methylpyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (370 mg, 1.52 mmol) in IMS (5 mL) was added a 1M aqueous solution of sodium hydroxide (2.0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and a 0.1M aqueous solution of HCl. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (348 mg, 100%). 1H NMR (400 MHz, CHCl3-d): 6 3.85-3.75 (m, 1H); 3.52-3.41 (m, 2H); 3.27-3.15 (m, 1H); 2.39-2.30 (m, 1H); 1.83-1.74 (m, 1H); 1.51-1.40 (m, 9H); 1.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][C@H:27]([N:30]([CH3:32])[CH3:31])[CH2:26]2)=[N:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].CNCCNC.Cl>O1CCOCC1.CCOC(C)=O.C(Cl)Cl.CCO.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([C:19]4[CH:24]=[N:23][C:22]([N:25]5[CH2:29][CH2:28][C@H:27]([N:30]([CH3:32])[CH3:31])[CH2:26]5)=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Reactant: CN(C)[C@H]1CCN(c2ccc(Br)cn2)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)[C@H]1CCN(c2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 116.4 %

Procedure:
Combine 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (0.2575 g, 0.98 mmol), [(S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine (Goodfellow, V.; et. al. US 2005012853) (0.3184 g, 1.18 mmol), and Cs2CO3 (0.64 g, 1.96 mmol) in dioxane (25 mL). Degass the suspension by purging with nitrogen for 5 min. Add CuI (37 mg, 0.20 mmol) and N,N′-dimethylethylenediamine (35 mg). Stir the reaction mixture at 100° C. overnight. Cool to RT and dilute with EtOAc (100 mL). Wash with a solution of H2O/NH3.H2O (2×30 mL/2 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify the crude material by chromatography by eluting with 2% NH3.H2O, 50% CH3OH/EtOAc to provide 0.258 g. Dissolve the material in CH2Cl2 (5 mL) and treat with 1.0 M HCl in EtOH (0.57 mL) to provide 0.278 g (58%) of the title compound. LC-MS/ES m/z (35Cl) 451.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1>[Pd].O1CCOCC1>[NH2:10][C:4]1[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccc(C#N)c(N)c1
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 4-methyl-2-nitrobenzonitrile (4.9 g, 30 mmol) and 10% palladium on carbon (500 mg) in 1,4-dioxane (60 mL) was stirred under hydrogen (balloon) overnight. The catalyst was removed by filtration through the Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane) to give the title compound as a pale yellow solid (3.3 g, 83%). 1H-NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.3 Hz, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 4.32 (br s, 2H), 2.29 (s, 3H).
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7]O)([O-:3])=[O:2].P(Br)(Br)[Br:11]>C1C=CC=CC=1>[Br:11][CH2:7][CH:6]=[C:5]([CH3:9])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CC(=CCO)C[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: CC(=CCBr)C[N+](=O)[O-]

Procedure:
To a solution of 0.1 Mol 4-nitro-3-methyl-2-butenol in benzene at 5° C. was added dropwise 0.036 Mol of phosphorous tribromide. The solvent was evaporated and the dark residue distilled through a vigreux column. Bp 100°/1 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH2:23]([O:30][CH:31]1[CH2:36][CH:35]([O:37][CH3:38])[O:34][CH:33]([CH2:39][CH2:40][NH2:41])[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH:31]1[CH2:36][CH:35]([O:37][CH3:38])[O:34][CH:33]([CH2:39][CH2:40][N:41]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:32]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: COC1CC(OCc2ccccc2)CC(CCN)O1
Product: COC1CC(OCc2ccccc2)CC(CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-(4-(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)ethanamine.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH:13]3[CH2:14][O:15]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: ClCC1CO1
Product: c1cc2c(cc1OCC1CO1)CCC2

Procedure:
The title compound was prepared from 5-indanol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[S-:11][S-:12].[Na+].[Na+]>O>[CH:5]1[CH:4]=[C:3]([N+:8]([O-:10])=[O:9])[C:2]([S:11][S:12][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:7][CH:6]=1.[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: [S-][S-]
Agent: O=[N+]([O-])c1ccccc1Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1SSc1ccccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
2500 parts of molten 1-chloro-2-nitrobenzene are charged to a stirred reactor and 150 parts of castor oil ethoxylate (about 15 moles of ethylene oxide per 1 mole of ricinoleic acid) and 1300 parts of water are added. The batch is heated to 60° C. and emulsified by efficient stirring. The freshly prepared sodium disulfide solution is then introduced beneath the surface of the emulsion. A total amount of 2520 parts of disulfide solution is added, the rate of addition being initially about 300 parts per hour and, towards the end of the reaction, about 100 parts per hour. The ensuing reaction is slightly exothermic and by cooling the temperature is kept in a range of 60° to 65° C.. Aggregates of 2,2'-dinitrodiphenyl disulfide and 1-chloro-2-nitrobenzene formed during the reaction are comminuted with e.g. a dismembrator. Chloronitrobenzene and resultant disulfide are continuously dispersed in the reaction medium by vigorously stirring the reaction mixture. After the total amount of disulfide solution is present in the reaction vessel, stirring is continued until the reaction mass consists of individual yellow crystals and of colourless to tea-coloured mother liquor. The batch is then cooled to 40° C., and the product is isolated by filtration and washed with cold water until the washings are colourless, affording 2897 parts of 80% 2,2'-dinitrodiphenyl disulfide, corresponding to a yield of 95% of theory. Melting point: 182°-184° C. (lit.: 196° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.ClC1C(P(C2CCCCC2)C2CCCCC2)=C(C2C(OC(C)C)=CC=CC=2OC(C)C)C=CC=1.COC(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N:21]([CH3:20])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: CNc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1cccc(Cl)c1P(C1CCCCC1)C1CCCCC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 5 h
Yield: 77.3 %

Procedure:
A solution of 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (116 mg, 0.41 mmol), N-methylaniline (89 μL, 0.82 mmol), RuPhos (20 mg, 0.041 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,-1′-biphenyl)[2-(2-aminoethylphenyl)palladium(II), methyl-tert-butylether adduct (33 mg, 0.041 mmol) and NaOtBu (99 mg, 1.8 mmol) in toluene (2 mL) was evacuated and flushed with nitrogen. The mixture was stirred at 110° C. for 5 h. The mixtures was allowed to cool and then partitioned between EtOAc and water. The organic extract was washed with brine, dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; gradient elution with 5-20% EtOAc in petrol) gave the title compound (112 mg, 56%) as a colourless solid. MS: [M+H]+=354.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([F:33])[CH:24]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>C1COCC1>[F:33][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:9][CH2:8][Si@H:7]([CH2:1][CH3:2])[CH2:12][CH2:11]3)[CH2:14][CH2:15]2)[CH:28]=[CH:27][C:26]=1[O:29][CH:30]([F:31])[F:32]
Reactant: CO[SiH]1CCC([C@H]2CC[C@H](CCCCc3ccc(OC(F)F)c(F)c3)CC2)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(OC(F)F)c(F)c3)CC2)CC1

Procedure:
130 ml (0.13 moles) of a THF solution of 1M of ethylmagnesium bromide was dropped in a mixed solution of 42.9 g (10 mmols) of 1-methoxy-4-(trans-4-(4-(3-fluoro-4-difluoromethoxyphenyl)butyl)cyclohexyl)-1-silacyclohexane and 30 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 37.8 g (yield: 88.6%) of the intended trans isomer product.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])C(=O)C2=CC=CC=C12>C(O)C.O>[NH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCC/C=C\CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NC/C=C\CCCC(=O)O
Yield: 112.7 %

Procedure:
Hydrazine hydrate (0.19 ml) was added to a solution of (Z)-7-phtalimidohept-5-enoic acid (1.05 g) in ethanol (25 ml) and water (5 ml). The solution was refluxed for 3 hours and then the solvent was removed. The residue was suspended in water and the pH of the solution was adjusted to 5. The resulting precipitate was collected by filtration. The filtrate was evaporated to dryness and extracted with ethanol. The ethanol extracts were evaporated to dryness to give the title compound as an oil (0.62 g).