Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: BrCCCCBr
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 1,4-Dibrombutane were converted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow semisolid, MS: 320 [M−C4H8BrO].
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:26])[C@H:13]([CH2:14][S:15]2(=[O:22])=[O:21])[C@:12]2([CH3:23])[C@H:7]([C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.[CH3:27][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:27])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:26])[C@H:13]([CH2:14][S:15]2(=[O:22])=[O:21])[C@:12]2([CH3:23])[C@H:7]([C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dihydroxy-1,11,15,15-tetramethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (28) (8.0 g, 21 mmol) in CH2Cl2 (192 mL) and methanol (64 mL), (trimethylsilyl)diazomethane (2 M in diethyl ether, 16.9 mL, 33.8 mmol) was added in 2 mL increments every hour at room temperature under N2. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel (Hexanes/EtOAc, 2:1) to yield (1R,10R,11S,16S)-3-hydroxy-5-methoxy-1,11,15,15-tetramethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (30) (4.9 g, 58%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[CH:14][CH3:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=Cn1c(C)c(C)c2cnnc(NCc3ccccc3)c21
Yield: 31.5 %

Procedure:
The title compound (trans) was prepared as a beige powder in 31.5% yield in a similar procedure to that described in Example 44 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and benzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][N:12]([CH2:14][CH:15]([NH2:17])[CH3:16])[C:13]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][CH:15]([NH:17][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH3:16])[N:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)-c1c(cnn1CC(C)N)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2ccc3cnn(CC(C)NC(=O)C(F)(F)F)c3c2c1
Yield: 82.7 %

Procedure:
A solution of 0.86 g (3.34 mmol) of (RS)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indazol-1-yl)-1-methyl-ethylamine, 0.56 ml (4 mmol) of triethylamine and 0.56 ml (4 mmol) of ethyl trifluoroacetate in 60 ml of anhydrous methanol was stirred at room temperature for 50 hours. After removing the solvent in a vacuum, the residue was taken up with 70 ml of anhydrous dioxan, 0.8 g (3.5 mmol) of DDQ was added and the mixture was boiled under reflux for 3 hours. Subsequently, the reaction mixture was concentrated in a vacuum and the residue was purified by column chromatography on silica gel (dichloromethane/acetone 4:1). 0.97 g (82%) of (RS)-N-[2-(8-methoxy-1H-benz[g]indazol-1-yl)-1-methyl-ethyl]-trifluoroacetamide was obtained as a pale brown solid which was used in the next reaction without further recrystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:60]2[CH2:61][CH2:62][N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:56])[CH2:58][CH2:59]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCN(C(=O)OC(C)(C)C)CC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 4.9 %

Procedure:
With 2.00 g of the compound obtained in Example 219 and 3.3 g of piperazine-1-carboxylic acid tert-butyl ester as starting materials, 120 mg of the title compound (colorless oil) was obtained by a similar procedure to Example 227.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([CH2:42][C:43]([N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:38][CH2:37][N:36]([CH2:42][C:43]([N:45]4[CH2:46][CH2:47][CH2:48][CH2:49]4)=[O:44])[CH2:41][CH2:40]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCCC3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound. LC-MS: 692.3 [(M+H)+]
Reaction SMILES: CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:10].[Na+].[CH3:15][C:16]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:22][CH2:23][CH:24]=C)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:15][C:16]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:22][CH2:23][CH:24]=[O:10])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CCCC(C)(C(=O)OCC)S(C)(=O)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C(C)(CCC=O)S(C)(=O)=O
Reaction time: 18 h
Yield: 100.9 %

Procedure:
2,6-Dimethylpyridine (6.1 mL, 52.9 mmol, 2.0 equiv), osmium tetroxide (2.5% w/v solution in tert-butyl alcohol, 6.6 mL, 0.53 mmol, 0.02 equiv), and sodium periodate (23.1 g, 106 mmol 4.0 equiv) were added sequentially to a solution of ethyl 2-methyl-2-(methylsulfonyl)hex-5-enoate (6.2 g, 26.0 mmol, 1.0 equiv) in 1,4-dioxane-water (3:1, 0.27 L) at room temperature. After vigorously stirring overnight (approx. 18 h), the reaction was partitioned between dichloromethane (0.2 L) and water (0.2 L). The aqueous phase was extracted with dichloromethane (0.2 L). The combined organic phases were washed with brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the title compound as an oil (6.2 g). MS (GCMS) m/z 237 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.34 (t, J=7.22 Hz, 3H) 1.63 (s, 3H) 2.21-2.39 (m, 1H) 2.56 (s, 2H) 2.65-2.81 (m, 1H) 3.05-3.17 (m, 3H) 4.30 (q, J=7.15 Hz, 2H) 9.79 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4].[I-:42].[Na+].CCCCCC>CC(C)=O>[I:42][CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: [I-]
Reactant: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CBr
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CI

Procedure:
A solution of 2-bromo-N,N-dioleylacetamide (0.81 g; 1.27 mmol) and sodium iodide (0.76 g; 5.08 mmol) in acetone is refluxed overnight. Hexane (10 ml) is added and the precipitate is filtered off to give, after evaporating the filtrate under reduced pressure, 2-iodo-N,N-dioleylacetamide (0.87 g; 100%) in the form of a yellowish liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: N#Cc1cccc(N2CCNCC2)c1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cccc(N2CCN(CCCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-cyanophenyl piperazine (5.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.7 g compound (I-10) with a yield of 62.4%. ESI-MS [M+H]+: m/z 360.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>C(OCC)(=O)C.CCCCCC.O1CCCC1>[C:20]1([C:8]2([C:9]3[CH:10]=[C:11]([B:32]([OH:35])[OH:33])[CH:12]=[CH:13][CH:14]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:3]3[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB(O)c1cccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
In a 100 mL three-neck flask was put 1.4 g (3.6 mmol) of 9-(3-bromophenyl)-9-phenyl-9H-fluorene. The air in the flask was replaced with nitrogen. Then, 36.0 mL of tetrahydrofuran was added to the mixture, and the mixture was stirred at 80° C. for 30 minutes. After the stirring, 2.4 mL (4.0 mmol) of a 1.65 mol/L hexane solution of n-butyllithium was dripped with a syringe, followed by stirring at −80° C. for 2 hours. Then, 0.6 mL (4.8 mmol) of trimethyl borate was added, and the mixture was stirred overnight while the temperature thereof was gradually increased from −80° C. to room temperature. After the stirring, an aqueous solution of hydrochloric acid (1 mol/L) was added to this mixture, and it was then stirred at room temperature for 30 minutes. Then, ethyl acetate was added to separate the organic layer and the aqueous layer of this mixture, and the aqueous layer was extracted with ethyl acetate three times. This ethyl acetate layer and the organic layer were combined, washed with saturated brine, and dried with magnesium sulfate. The obtained mixture was gravity filtered so that magnesium sulfate was removed, and the obtained filtrate was concentrated to give a white solid. Recrystallization of the obtained white solid from a mixed solvent of ethyl acetate and hexane gave 1.2 g of a white solid in 90% yield, which was the substance to be produced. The synthesis scheme of this Step 1 is shown in (E18-1) given below.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Cl)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dimethoxybenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2,3-dimethoxybenzoyl chloride.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nnc(Cc3ccc(C4CCNCC4OCc4ccc5ccccc5c4)cc3)o2)cc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine trifluoroacetate as a white powder; MS: 476 (M+H)+.
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[CH3:60][O:61][C:62]1[CH:63]=[CH:64][C:65]2[CH2:71][CH2:70][CH:69]([N:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:68][CH2:67][C:66]=2[C:78]=1[NH2:79]>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:79][C:78]2[C:66]3[CH2:67][CH2:68][CH:69]([N:72]4[CH2:73][CH2:74][O:75][CH2:76][CH2:77]4)[CH2:70][CH2:71][C:65]=3[CH:64]=[CH:63][C:62]=2[O:61][CH3:60])=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)CCC(N1CCOCC1)CC2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCC(N1CCOCC1)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with 2-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine to afford N-{(1R,2R)-2-[5-Chloro-2-(2-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (Diasteromeric Mix). LC/MS (ESI): 579.24. 1H NMR (400 MHz, DMSO, d6) δ 9.85 (m, 1H), 7.17 (m, 1H), 6.88 (m, 1H), 3.94 (m, 3H), 3.70 (s, 3H), 3.28 (m, 3H), 3.20 (m, 6H), 2.88 (s, 3H), 2.72 (m, 2H), 1.99 (m, 4H), 1.67 (m, 2H), 1.41 (m, 2H), 1.21 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([NH:9]C)[CH:6]=[CH:7][CH:8]=1.[C:14](OCC)(=O)C>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:4]=1[NH:11][CH3:14]
Reactant: CCOC(C)=O
Reactant: CNc1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1c(N)cccc1OC
Reaction time: 4.5 h

Procedure:
7.4 g (3-methoxy-2-nitrophenyl)-methylamine are suspended in 150 ml of ethyl acetate and hydrogenated with 1 g Pd/C 10% at a pressure of 50 psi and at ambient temperature. After 4.5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 5.9 g of the product are obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:27]([O:31][CH2:32]C)[O:28][CH2:29]C)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:27]([O:28][CH3:29])[O:31][CH3:32]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(Br)c(C(OC)OC)c1
Yield: 53 %

Procedure:
Step AH (2): 2-Bromo-5-methoxybenzaldehyde (1069 mg, 4.975 mmol) was dissolved in a mixture of methanol (20 mL) and triethylorthoformate (20 mL). p-Toluenesulfonic acid monohydrate (180.0 mg, 0.946 mmol) was added and the reaction mixture was stirred under reflux for 5 h. The reaction was quenched with aqueous NaHCO3 and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum at the temperature, not exceeding 35° C. The residue was purified by silica gel chromatography to give 1-bromo-2-(dimethoxymethyl)-4-methoxybenzene (688.5 mg, 53%) as colorless oil. LC-MS (M+H)+=261.00. 1H NMR (CDCl3, 500 MHz) δ 7.42 (d, J=7.0 Hz, 1H) 7.16 (d, J=3.0 Hz, 1H) 6.76 (dd, J1=10 Hz, J2=3.0 Hz, 1H) 5.50 (s, 1H) 3.80 (s, 3H) 3.39 (s, 6H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].I[CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:27]([O:26][C:24]([C:21]1([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of potassium hexamethyldisilazide (29.1 g, 146 mmol) in THF (200 mL) at −78° C. was added ethyl N-Boc-piperidine-4-carboxylate (25 g, 97 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then 1-iodopropane (14.2 mL, 146 mmol) was slowly added. The reaction mixture was stirred at −78° C. for a further 20 minutes, then warmed to room temperature and stirred for 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (0% to 50% EtOAc in hexanes) to afford 19.3 g (66%) of 4-propyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=[N:23]C2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13]([NH2:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(4-methylphenyl sulfonamido)pent-4-ynoic acid (1.0 g, 3.7 mmol), HOAt (0.76 g, 5.6 mmol), iPr2NEt (2.17 g, 16.9 mmol), NH4Cl (0.6 g, 11 mmol), and EDCI (1.07 g, 5.61 mmol) in 20 mL DMF was stirred for 18 h at RT. Water was added, which caused a precipitate to form. The white solid was filtered and air dried to afford the title compound. MS (m/z, m+1): 267.3.
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28](O)=O)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>>[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[O:20][N:19]=[C:2]([C:3]3[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:5]([F:18])[CH:4]=3)[N:1]=2)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)cc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 49 (142.14 mg; 0.50 mmol) and Intermediate 3 (135.76 mg; 0.60 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a colorless oil. LC/MS (Method B): 475.4 (M+H)+. HPLC (Method A) Rt 6.78 min (Purity: 99.3%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)n(-c2ccccc2)n1

Procedure:
118 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75 mg, 0.310 mmol), 1-(4-chlorophenyl)piperazine (83 mg, 0.310 mmol), DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)3 (197 mg, 0.930 mmol).