Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:22]12([N:32]=[C:33]=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:33](=[O:34])[NH:32][C:22]34[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]3)[CH2:29]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Product: CCOC(=O)CC1CC2(CCN(C(=O)NC34CC5CC(CC(C5)C3)C4)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared from (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 1-adamantyl isocyanate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR=2.32 min, m/z=531; 1H NMR (CDCl3) δ=7.38 (d, 1H), 7.12-7.04 (m, 2H), 4.19 (q, 2H), 3.87 (m, 2H), 3.57 (m, 1H), 3.13-2.83 (m, 4H), 2.63 (dd, 1H), 2.44 (m, 2H), 1.42 (d, 2H), 1.29 (t, 3H).
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31].[H-].[Na+].S(OC)(O[CH3:38])(=O)=O.O>COCCOC>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:38])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2Cl)C1=N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2Cl)C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.52 g.; 0.01 mol) in 1,2-dimethoxyethane (50 ml.) there is added 57% sodium hydride (0.42 g.; 0.01 mol) (oil dispersion). The mixture is stirred at room temperature for one hour and there is then added dimethyl sulfate (1.26 g.; 0.01 mol). The mixture is stirred at room temperature for one hour and is poured into an excess of water. The suspension is filtered and the filter cake dried to afford 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1>O>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([NH:14][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:3]=[N:4][CH:5]=1
Reactant: NC1CCC1
Reactant: Nc1c(Cl)cnnc1Cl
Solvent: O
Product: Nc1c(Cl)cnnc1NC1CCC1
Temperature: 125 °C
Yield: 58 %

Procedure:
A mixture of 3,5-dichloro-4-aminopyridazine (Preparation 4, 200 mg, 1.22 mmol), cyclobutyl amine (0.56 mL) and water (1.12 mL) was heated under microwave irradiation at 125° C. for 4 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 58% yield, 140 mg.
Reaction SMILES: [OH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[Na+]>C(Cl)(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[O:1][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cccs1
Yield: 19.4 %

Procedure:
To a solution of 2-hydroxy-thiophene (32 g, 320 mmol) in CHCl3 (500 mL) is added ethyl bromoacetate (53.4 g, 320 mmol). To the resulting solution is added a solution containing n-Bu4NHSO4 (25 g, 74 mmol) and NaOH (15.8 g, 394 mmol) in water (500 mL). After addition, the solution is stirred vigorously using mechanical stirring. The reaction is stirred for 12 hours. After this time, the layers are separated. The aqueous layer is extracted with CHCl3. The combined organic layers are washed with water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated under vacuum. The resulting crude product is purified by column chromatography eluting with a gradient of 30%CH2Cl2:hexanes to 60%CH2Cl2:hexanes. The title compound (11.5 g, 62 mmol) is obtained as 1H NMR (CDCl3, 300 MHz) δ6.68 (dd, 1H), 6.60 (d, 1H), 6.22 (d, 1H), 4.62 (s, 2H), 4.30 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C@H:15]3[C@@H:19]([CH2:20]O)[O:18][C:17]([CH3:23])([CH3:22])[O:16]3)=[O:14])[CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[NH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C@H:15]3[C@@H:19]([CH2:20][Br:54])[O:18][C:17]([CH3:23])([CH3:22])[O:16]3)=[O:14])[CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[NH:3]1
Reactant: CC1(C)O[C@H](CO)[C@H](C(=O)Nc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)O1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)O[C@H](CBr)[C@H](C(=O)Nc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 176.3 %

Procedure:
The (4R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-carboxylic acid [1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]amide (1.5 g, 3.24 mmol) obtained in step A was dissolved in an anhydrous methylene chloride solution (30 ml). Thereafter, triphenylphosphine (2.21 g, 8.43 mmol) and carbon tetrabromide (2.80 g, 8.43 mmol) were added to the solution, and the obtained mixture was stirred at a room temperature for 3 hours. Thereafter, the solvent was distilled away. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1), so as to obtain (4R,5S)-5-bromomethyl-2,2-dimethyl-[1,3]dioxolan-4-carboxylic acid [1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]amide (3.0 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:14][C:12]=2[CH:13]=1.[Br:26]Br.[O-]S([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[Br:26][C:13]1[C:12]2[CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)[CH:16]=[CH:17][C:11]=2[O:10][C:9]=1[CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: BrBr
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCCN1CCc1oc2ccc(-c3ccc(C#N)cc3)cc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
The product from Example 1D (2.5 g (5.2 mmol) and trifluoroacetic acid (40 mL) (TFA) were combined and stirred at 25° C. for 10 min. The mixture was slowly treated with a solution of Br2 (450 μL, 7.8 mmol) in TFA (10 mL). The mixture was allowed to stir at 25° C. for 1 h and then treated with saturated aqueous Na2SO3. The mixture was concentrated and redissolved in 50 mL ethyl acetate. The organic phase was washed with 1M NaOH, dried, and concentrated under reduced pressure to provide the title compound (2.1 g, 97% yield). 1HNMR (300 MHz, CD3OD) δ 1.16 (d, 3H, J=6.1 Hz), 1.42 (m, 1H), 1.78 (m, 2H), 1.98 (m, 1H), 2.32 (m, 1H), 2.50 (m, 2H), 3.11 (m, 2H), 3.28 (m, 2H), 7.58-7.70 (m, 3H), 7.82 (m, 4H); MS (ESI) m/e 409 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH2:22][N:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1.C([O-])([O-])=O.[K+].[K+].O>CN1CCN(C)C1=O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH2:22][N:23]1[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:24]1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: COc1cccc(CN2CC[C@@H](N)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc(OC)c3)C2)cn1
Temperature: 106 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (278 mg) in 1,3-dimethyl-2-imidazolidinone (2.78 mL) was added (3R)-1-(3-methoxybenzyl)-3-pyrrolidinamine dihydrochloride (547.5 mg) and K2CO3 (1.08 g), which was stirred at 106° C. for 3 hours. To the resultant was added H2O, which was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (367.5 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([N+:24]([O-])=O)[CH:16]=1.[NH2:27][CH2:28][CH2:29][C:30]#N.C([O-])(=O)/C=C/C([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:16][C:17]=1[NH:24][CH2:30][CH2:29][C:28]#[N:27])([O-:23])=[O:22]
Reactant: CC(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Cl)c1
Reactant: N#CCCN
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(NCCC#N)c2)c(Cl)c1
Yield: 70.9 %

Procedure:
A solution of 4.0 g of 2-chloro-4-isopropylsulphonyl-(3,4-dinitrophenoxy)benzene and 3.85 g of 3-aminopropionitrile. 0.5 fumarate in 100 ml of acetonitrile, to which 4.1 g of potassium carbonate was added, was refluxed for 6 hours. After evaporation the residue was dissolved in methylenechloride an extracted with water. After washing with water the organic layer was filtered and reduced. Recrystallisation from methanol yielded 3.0 g of the desired product; m.p. 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]1[CH:13]=[CH:14][C:15]2[S:19][CH2:18][CH2:17][C:16]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH2:18][CH2:17][C:16]=3[CH:20]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccc2c(c1)CCS2
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1ccc2c(c1)CCS2
Temperature: 90 °C
Yield: 61.8 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5-hydroxy-2,3-dihydrobenzothiophene (prepared as described in Synth. Commun. 1991, 21, 959-964) (808 mg, 5.31 mmol) and K2CO3 (1.47 g, 10.6 mmol) in DMF (5 mL) was heated at 90° C. for 16 h. After cooling to room temperature the mixture was partitioned between water (50 mL) and ether (50 mL), the aqueous layer being extracted with ether (50 mL). The combined organic extracts were washed with water (50 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; 9:1 (pentane/EtOAc)], then triturated with ether, to give the product (1.1 g, 62%) as a pale yellow solid; δH (CDCl3, 400 MHz) 3.28 (2H, t), 3.41 (2H, t), 6.78 (1H, d), 6.84 (1H, d), 6.92 (1H, s), 7.20 (1H, d), 7.58 (1H, d), 8.00 (1H, s), 10.43 (1H, s).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([NH2:16])(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13]([N:16]=[CH:19][N:20]([CH3:22])[CH3:21])(=[O:15])=[O:14])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(C)(C)C)cc1S(N)(=O)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)C)cc1S(=O)(=O)N=CN(C)C
Reaction time: 0.5 h

Procedure:
4.68 g (0.02 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonamide are dissolved in 50 ml of dimethylformamide, and 2.5 g (0.022 mol) of dimethylformamide dimethyl acetal are added. The mixture is left at room temperature for 30 minutes, then poured onto ice-water and filtered with suction.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.06 g, 7.51 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.24 g, 11.26 mmol) in 20 mL 1,2-dichloroethane was treated with sodium triacetoxyborohydride (4.77 g, 22.53 mmol) then acetic acid (1.28 mL, 22.53 mmol). The suspension was stirred at room temperature overnight. At this time, a TLC analysis indicated that 1,2,3,4-tetrahydroquinoline is present along with a more polar spot. To the reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (1.12 g, 5.63 mmol) and sodium triacetoxyborohydride (2.39 g, 11.28 mmol). The suspension was stirred at room temperature for 4 days. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with 50 mL CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated to give a yellow residue. This residue was purified by the Biotage purification system using a silica gel 40M column. A gradient of 5% ethyl acetate:hexanes to 30% ethyl acetate:hexanes over 10 column volumes was used to give the title compound (0.89 g, 37.4%). 1H-NMR (CDCl3) δ 7.09-7.03 (m, 1H), 6.97-6.94 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.60-6.55 (m, 1H), 4.30-4.19 (m, 2H), 3.80-3.70 (m, 1H), 3.17 (t, J=5.7 Hz, 2H), 2.84-2.71 (m, 2H), 2.73 (t, J=6.3 Hz, 2H), 1.93-1.85 (m, 2H), 1.78-1.63 (m, 4H), 1.48 (s, 9H). MS (ESI): 317.2 (M+1).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH3:15])=O)(C)(C)C.C([Li])(C)(C)C.CON(C)C(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:6]2[NH:8][C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[CH:15]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Product: c1ccc(-c2cc3cnccc3[nH]2)cc1

Procedure:
4-tert-Butoxycarbonylamino-3-methylpyridine (Example 11a, 1.0 g, 4.8 mmol) was dilithiated with t-butyllithium and treated with N-methoxy-N-methylbenzamide (0.95 g, 5.76 mmol) as described previously. The crude product was purified by trituration with ethyl acetate to afford the title compound as a pale beige solid; yield: 0.59 g (63%); mp 276°-278°C.[Lit. mp 282°-283° C.].
Reaction SMILES: O.NN.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:7][CH2:6]1>C(O)C.[Ni]>[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][CH2:6]1
Reactant: CN1CCN(Cc2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2ccccc2N)CC1
Reaction time: 2 h

Procedure:
In 30 volume parts of ethanol is dissolved 1.87 parts of N1 -methyl-N4 -(2-nitrobenzyl)piperazine, followed by the addition of 3.0 parts of Raney nickel. Then, 3.0 parts of hydrazine hydrate is further added to the mixture and the entire mixture is kept at room temperature for 2 hours. Following this reaction, the Raney nickel is filtered off and the solvent is distilled off under reduced pressure. The residual oily substance is recrystallized from aqueous methanol. The procedure gives pale yellow crystals melting at 78° to 79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[K+].C(#N)C.S1(CCCC1)(=O)=O.O(Cl)[Cl:27]>O.CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1Cl
Reactant: ClOCl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixed solution containing 1,280 g of potassium 4-chloro-3-nitrobenzenesulfonate, 1,150 ml of acetonitrile, 250 ml of Sulfolane (tetrahydrothiophene 1,1-dioxide) and 30 ml of dimethylacetamide was dropwise added 1,250 ml of phoshporus oxychloride under an inside temperature at 60° C. to 70° C. After the reaction was continued for 3 hours at 73° C., the reaction mixture was cooled with water, and thereto was slowly added 400 ml of water. The thus obtained product was poured into 5 liters of ice-cold water. The crystalline precipitate was filtered off, washed with water, and dried.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:72])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([O:62][Si](C(C)(C)C)(C)C)[CH:58]=4)[CH:53]=3)[CH:47]([O:70][CH3:71])[CH2:46]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:72])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([OH:62])[CH:58]=4)[CH:53]=3)[CH:47]([O:70][CH3:71])[CH2:46]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O)ccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h

Procedure:
To a stirred solution of 17-ethyl-20-fluoro-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH2Cl2 (2 mL) was added a solution of p-toluenesulfonic acid in methanol (2 mL, 10% solution). The flask is capped and the mixture stirred 4 hours. The reaction is quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts are combined and dried over anhydrous Na2SO4. The mixture is filtered and concentrated in vacuo. The product is isolated by preparative TLC on silica gel to afford the title compound.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15](N(OC)C)=[O:16])=[CH:13][CH:12]=2)=[N:9][CH:10]=1>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15](=[O:16])[CH3:1])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(F)cn2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in tetrahydrofuran) (2.1 mL, 6.2 mmol) was added to a −78° C. solution of 4-(5-fluoropyridin-2-yl)-N-methoxy-N-methylbenzamide (800 mg, 3.1 mmol) in tetrahydrofuran (20 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with methanol and saturated aqueous ammonium chloride. The organic layer was dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-15% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: N#Cc1cccc(CBr)c1
Product: N#Cc1cccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 3-bromomethyl-benzonitrile (CAS Reg. No. 28188-41-2). Light brown sticky solid (76%). MS (Turbo Spray): m/z=492.2 (M+H).
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13]C)[CH:9]=[CH:10][C:11]=2[CH:12]=1>Br>[OH:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([CH3:1])[C:15]([OH:17])=[O:16])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Br
Product: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reaction time: 0.5 h

Procedure:
A mixture of Naproxen (500 g, 2.774 mmol) and 48% HBr (1500 ml) was refluxed for 10 hours, poured onto ice water (3000 ml) and stirred for 30 minutes. Crude 5 was filtered, dried (380 grams, 81%) and used as such for next stage.
Reaction SMILES: [C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]([O:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2].[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])=[C:11]([O:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2]
Reactant: COc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1C(=O)O)C(=O)OC2
Yield: 930 %

Procedure:
A solution of 3.88 g (11.1 mmol) of (E)-6-(1,3-dihydro-4-carboxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and 0.2 g (1.0 mmol) of p-toluene sulfonic acid in methanol (60 ml) was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and this solution was washed twice with water, once with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid which was recrystallized from ethyl acetate to give 3.37 g (9.3 mmol) of methyl (E)-6-(1,3-dihydro-4-carboxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 169°-170° C.