Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].O.[NH2:14][NH2:15]>O>[F:1][C:2]1[CH:12]=[C:6]([C:7]([NH:14][NH2:15])=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(F)c1
Reactant: NN
Solvent: O
Product: NNC(=O)c1cncc(F)c1
Yield: 83 %

Procedure:
A mixture of 6.7 g of ethyl 5-fluoronicotinate (cf. U.S. Pat. No. 3,637,714) and 6.0 g of hydrazine monohydrate is stirred at 110° C. for 2 hours. After cooling, 30 ml of cold water is added, and the precipitate is collected and washed with cold water to give 5.1 g of crude 5-fluoro-3-pyridinecarbohydrazide. To a stirred mixture of 5.1 g of the hydrazide in 40 ml of pyridine, 6.9 g of p-toluenesulfonyl chloride is added slowly. After the mixture becomes a clear solution, the remaining pyridine is distilled off under reduced pressure, and 30 ml of water is added. The resulting precipitate is collected and washed with water to give 6.6 g of the crude p-toluenesulfonyl derivative. The product is added to 40 ml of ethylene glycol at 120° C., and to the mixture is added with stirring 6.5 g of anhydrous sodium carbonate. The reaction mixture is stirred at 160° C. for 10 minutes and cooled, and 50 ml of water is added. The mixture is extracted with three 100-ml portions of diethyl ether. The combined extracts are dried over magnesium sulfate and concentrated to give 1.1 g of crude 5-fluoro-3-pyridinecarbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:4]([N+:15]([O-])=O)[CH:3]=1>C(O)C.[Ni]>[NH2:15][C:4]1[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=1[NH:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1NC1CCCCC1
Yield: 103.7 %

Procedure:
41.6 g (0.16 mol) of 4-chloro-N-cyclohexyl-2-nitroaniline were dissolved in 400 ml of ethanol and, after addition of 4.2 g of Raney nickel, hydrogenated under 1 bar at 25° C. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 37.3 g (100%) of the product.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]3)[CH2:6][CH2:5]2)[N:20]=1
Reactant: O[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: Cc1ccnc(Cl)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCN([C@H]3CC[C@H](O)CC3)CC2)n1

Procedure:
The compound 10a (4.3 g, 23.3 mmol) is placed in 100 ml of toluene in the presence of 2-chloro-4-methylpyrimidine (3 g, 23.3 mmol) and of triethylamine (4.9 ml, 35.1 mmol) and then this mixture is heated at reflux for 16 h.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>C1COCC1>[C:5]([Si:2]([CH3:4])([CH3:3])[CH3:1])#[C:6][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH2:8]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCCCCCCBr
Solvent: C1CCOC1
Product: C=CCCCCCCC#C[Si](C)(C)C
Temperature: 0 °C
Yield: 16.2 %

Procedure:
A 250-mL round-bottom flask equipped with a stir bar and a water-jacketed reflux condenser was charged with trimethylsilylacetylene (6.00 mL, 42.0 mmol). THF (50 mL) was added, and the mixture was allowed to cool to 0° C. (ice-bath). nButyllithium (29.0 mL, 42.0 mmol, 1.46 M solution in hexanes) was added dropwise by a syringe, and the ice-bath was removed following the addition. The mixture was allowed to warm to 22° C. as it stirred for 1 h, at which point 8-bromo-1-octene (3.50 mL, 21.0 mmol) was added, and the mixture was allowed to reflux for 12 h. The mixture was allowed to cool to 0° C., quenched by addition of 50 mL water, washed with CH2Cl2 (5×50 mL). The combined organic layers were washed in brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting brown oil was filtered through a plug of silica gel (eluted in pentane), the filtrate was concentrated and the resulting brown oil distilled under vacuum (1.0 torr). The resulting yellow oil was re-distilled under vacuum (1.0 ton) to afford dec-9-en-1-ynyltrimethylsilane (0.700 g, 3.40 mmol, 14.0% yield) as a colorless oil. IR (neat): 3078 (w), 2929 (m), 2857 (w), 2175 (m), 1641 (w), 1461 (w), 1325 (w), 1248 (m), 1032 (w), 994 (w), 910 (m), 837 (s), 758 (s), 725 (w), 697 (w), 638 (m), 575 (w), 450 (w); 1H NMR (400 MHz, CDCl3): δ 5.86-5.76 (1H, m), 4.99 (1H, dd, J=17.2, 2.0 Hz), 4.93 (1H, dd, J=10.0,0.8 Hz), 2.21 (2H, t, J. 7.2 Hz), 2.05 (2H, app q, J=7.1 Hz), 1.55-1.48 (2H, m), 1.40-1.28 (6H, m), 0.14 (9H, s); 13C NMR (100 MHz, CDCl3): δ 139.2, 114.4, 107.8, 84.4, 33.9, 28.9, 28.8, 28.7, 28.7, 20.0, 0.3; HRMS (ESI+) [M+H]+ calcd for C13H25Si: 209.1726, found: 209.1719.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:41]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:45][NH:44][CH:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>C(N(CC)CC)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:44]1[CH2:45][CH2:46][N:41]([C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[CH2:42][CH:43]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Yield: 383.1 %

Procedure:
3-((6-Chloro-2-naphthyl)sulfonyl)propanoic acid (0.33 g), HOBt (2.30 g) and WSC (2.88 g) were added to acetonitrile (50 mL) and mixed for 15 minutes. Then, di-tert-butyl piperazine-1,3-dicarboxylate (2.99 g) and triethylamine (3.03 g) were added thereto, and the mixture was mixed at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and an aqueous potassium carbonate solution. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (2.40 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][NH:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N([CH2:29][CH3:30])CC)C>C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][N:13]([C:15]([O:17][CH2:18][C:30]3[CH:29]=[CH:9][CH:8]=[CH:7][CH:21]=3)=[O:16])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of ethyl 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-azaspiro[4.5]decane-3-carboxylate (110) (10.61 g, 31.3 mmol) dissolved in dry DCM, triethylamine was added (10.8 mL, 78 mmol), cooled to 0° C. followed by the addition of Cbz-CI (6.2 mL, 43.5 mmol), and the reaction stirred at 0° C., for 5 min, rt for 1 h. Reaction diluted with DCM (700 mL), washed with 0.1 N HCl (700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-60% hexanes/EtOAc to afford the title compound as a yellow oil (5.73 g, 39% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[N:11][C:4]=2[NH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[OH:13][CH2:12][C:10]1[CH:9]=[CH:8][C:5]2[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[N:11]=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CSc2ccc(CO)nc2N1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500 mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to −10° C. and isobutyl chloroformate (0.339 ml) was added. After 20 minutes the suspension was filtered through kieselguhr into an ice-cooled solution of sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes and the pH reduced to 7 with dilute HCl. The solvent was evaporated and the residue triturated under water. The product was filtered and dried under vacuum to give a white solid (346 mg); LC/MS (APCI−) m/z 195 ([M−H]−, 50%), 165(100%).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 37.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 1-azetidin-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.7 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:7]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(Br)ccc3O)nc3ccccc23)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Oc1ccc(-c2ccc(F)cc2)cc1-c1nc(N[C@H]2CCNC2)c2ccccc2n1
Reaction time: 16 h
Yield: 27 %

Procedure:
(S)-tert-Butyl 3-(2-(5-bromo-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.051 g, 0.105 mmol, prepared in a method analogous to that described in Synthesis 2-A), 4-fluorobenzene boronic acid (0.016 g, 0.114 mmol), palladium tetrakistriphenyl phosphine (0.028 g, 0.024 mmol) and potassium phosphate (0.051 g, 0.243 mmol) were dissolved in dimethyl acetamide (0.7 mL) and water (0.3 mL) and the mixture was heated in a microwave for 10 mins at 150° C. The mixture was filtered through a short plug of silica using ethyl acetate as eluent and the filtrate concentrated in vacuo. The residue was dissolved in methanol (1.2 mL) and 4M HCl in dioxane (1.2 mL) was added and the mixture stirred for 16 h. The mixture was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by silica column chromatography, eluting with dichloromethane then 10% methanol in dichloromethane, to give the title compound as a yellow solid (0.013 g, 27%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=O)[NH:16][C:17]=1[CH3:18]>C(O)(=O)C.CCO>[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[NH:16][C:17]=1[CH3:18]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1Br
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1[nH]c(C=NNC(=O)c2ccc(O)cc2)c(C)c1Br
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.06 g, 0.0004 mol) and 4-bromo-3,5-dimethyl-pyrrole-2-carboxaldehyde (0.08 g, 0.0004 mol) in abs. EtOH (5 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.1 g, in 77% yield, mp: 235.4° C. 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 11.21 (s, 1H), 9.99 (s, 1H), 8.26 (s, 1H), 7.76 (d, 2H), 6.82 (d, 2H), 2.15 (s, 3H), 2.03 (s, 3H). 13C NMR (DMSO-d6) δ 163.9, 162.2, 140.2, 131.6, 131.3, 126.1, 124.0, 124.3, 116.8, 13.4, 11.8. Anal. Calcd for C14H14BrN3O2 ·¼ H2O: C, 49.35; H, 4.14; N, 12.33; Br, 23.69. Found: C, 49.21; H, 3.95; N, 11.96; Br, 23.37.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>C(#N)C>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[N:4]=[CH:3]1
Reactant: C1CSCCN1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)N2CCSCC2)c1
Reaction time: 6 h

Procedure:
2 g (11 mmol) of 1-methyl-4-imidazolesulfonyl chloride from Example C-1, dissolved in 20 ml of acetonitrile, are added dropwise with stirring at room temperature to a solution of 1.51 ml (15 mmol) of thiomorpholine in 50 ml of acetonitrile. The reaction mixture is subsequently stirred for 6 hours, filtered and evaporated in vacuo. The residue remaining is recrystallized from isopropanol in order to give the title compound of melting point 154°-155° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:31]([NH:23][S:20]([C:18]2[CH:17]=[CH:16][C:13]3[CH2:14][CH2:15][N:9]([C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=2)(=[O:22])=[O:21])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCCC1)CC2
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-(1-piperidinylcarbonyl)-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-{[2,3,4,5-tetrahydro-3-(1-piperidinylcarbonyl)-1H-3-benzazepin-7-yl]sulfonyl}urea, m.p. 166°-167° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with 1-piperidine-carbonyl chloride in a manneranalogous to that described in Example 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([OH:20])=[CH:10][N:9]=1.Br[CH2:22][CH:23]([F:25])[F:24]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([O:20][CH2:22][CH:23]([F:25])[F:24])=[CH:10][N:9]=1
Reactant: FC(F)CBr
Reactant: COc1ccc2c(Cl)ncc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c(Cl)ncc(OCC(F)F)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Potassium carbonate (659 mg, 4.77 mmol) was added to a solution of 1-chloro-6-methoxyisoquinolin-4-ol (500 mg, 2.385 mmol) and 2-bromo-1,1-difluoroethane (346 mg, 2.385 mmol) and stirred for 3 hrs at 50° C. After 3 hrs, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1-chloro-4-(2,2-difluoroethoxy)-6-methoxyisoquinoline (538 mg, 82%) as an orange solid. Crude material used as is in next step. MS: MS m/z 274.1(M++1).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:38][C:39]([NH2:41])=[O:40].[Br-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH2:38][C:39]([NH2:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CC(N)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of the bishydrochloride salt of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treated with diisopropylethylamine (165 μL, 1.0 mmol) followed by 2-bromoacetamide (42 mg, 0.3 mmol). The reaction mixture was heated at 50° C. for 8 h and an additional amount of bromide (42 mg, 0.3 mmol) then added. The reaction mixture was then stirred for an additional 16 h at room temperature and evaporated. The crude reaction was then partitioned between EtOAc (3 mL) and a saturated aqueous NaHCO3 solution (3 mL). The organic phase was isolated and further washed with an additional portion of a saturated aqueous NaHCO3 solution (3 mL) and brine (2×3 mL).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH:17]2[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:19][CH:11]1[CH2:12]3)[CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][CH2:9][CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCOCC1C2CC3CC(C2)CC1C3
Product: O=[N+]([O-])c1ccc(CCCCCCCOCC2C3CC4CC(C3)CC2C4)cc1
Yield: 46.9 %

Procedure:
General procedure M was used to convert 2.77 mmol of 11d and 3.05 mmol of 1-bromo-4-nitrobenzene to 1.30 mmol (47%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:11](O)[CH3:12])[CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:14]([O:19]C)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[CH2:3]([N:2]([CH3:1])[CH2:11][CH2:12][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCC=CCN(C)C(C)O
Reactant: C=C(C)C(=O)OC
Product: C=CCCC/C=C/CN(C)CCOC(=O)C(=C)C

Procedure:
The resulting (methyl(octa-2,7-dienyl)amino)ethanol was subsequently reacted with methyl methacrylate to give 2-[((2-E)octa-2,7-dienyl)methylamino]ethyl-2-methylprop-2-enoate.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cu][C:15]#[N:16]>CN1C(=O)CCC1.CCOC(C)=O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:15]#[N:16])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 160 °C
Yield: 20.3 %

Procedure:
3-iodo-5-nitro-1H-indazole (6.9 g, 23.87 mmol) was taken up in NMP (90 mL) and copper (I) cyanide (4.28 g, 47.7 mmol) was added. The reaction was heated at 160° C. for 1 h, then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through celite, rinsing with EtOAc. The filtrate was washed 2× with water and 2× with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 0.91 g of 5-nitro-1H-indazole-3-carbonitrile was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:38][CH3:39])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(4-nitrobenzylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.89 g) as starting compound, acetaldehyde (0.11 ml) and sodium cyanoborohydride (0.25 g) were reacted and treated in the same manner as in Example 136 to give 0.4 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(4-nitrobenzyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Fc1ccccc1-c1cc(CCl)ccn1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccccc3F)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(2-fluorophenyl)pyridine (222 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [C:1]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([O:22][CH3:23])[C:6]=1[O:24][CH3:25])([O:3][CH3:4])=[O:2].[OH-].[Na+].[CH:28](O)=O>C=O>[C:1]([C:5]1[C:15]2[CH2:14][CH2:13][N:12]([CH3:28])[CH2:11][CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]([O:22][CH3:23])[C:6]=1[O:24][CH3:25])([O:3][CH3:4])=[O:2]
Reactant: O=CO
Reactant: COC(=O)c1c2c(cc(OC)c1OC)C(c1ccccc1)CNCC2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1c2c(cc(OC)c1OC)C(c1ccccc1)CN(C)CC2

Procedure:
A solution of 3.7 g of 6-carbomethoxy-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give 6-carbomethoxy-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.[CH2:31](Br)[CH:32]=[CH2:33]>>[CH2:33]([N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=2[CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:28])=[O:27])[CH:32]=[CH2:31]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: C=CCBr
Product: C=CCN1C(c2c(C)n(CC(=O)O)c3ccc(Cl)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and allyl bromide. 1H NMR (DMSO-d6) 13-14 (bs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.06 (d, J=6.3 Hz, 1H), 7.02 (dd, J=1.8, 8.7 Hz, 1H), 6.83 (s, 1H), 5.96 (s, 1H), 5.82-5.69 (m, 1H), 5.14 (d, J=7.5 Hz, 1H), 5.10 (s, 1H), 5.03 (s, 2H), 3.90 (dd, J=4.8, 15.9 Hz, 1H), 3.45-3.36 (m, 1H), 2.37 (s, 3H); MS: ESI (negative): 429, 431 (M−H).