Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2[C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2[C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(CO)o2)c1C(=O)NCCN1CCOCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(C=O)o2)c1C(=O)NCCN1CCOCC1
Yield: 27.4 %

Procedure:
A mixture of 4-(5-hydroxymethyl-2-furyl)-2-methyl-3-(2-morpholinoethylcarbamoyl)-6-phenylpyridine (4.4 g) and activated manganese dioxide (26 g) in ethyl acetate (100 ml) was refluxed for 3 hours under stirring. Manganese dioxide was filtered off and the filtrate was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The column was eluted with a mixture of ethyl acetate and tetrahydrofuran (7:3 V/V) and the fraction was evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give 4-(5-formyl-2-furyl)-2-methyl-3-(2-morpholinoethylcarbamoyl)-6-phenylpyridine (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:18](OC4C=CC([N+]([O-])=O)=CC=4)=[O:19])[CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[N:3]=1.[C:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:4]2[CH:5]=[C:6]([C:8]3[CH:17]=[C:12]4[C:11]([CH2:16][CH2:15][N:14]([C:18]([N:46]5[CH2:47][CH2:48][CH:43]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:44][CH2:45]5)=[O:19])[CH2:13]4)=[CH:10][CH:9]=3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:31][CH2:32]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC4)nc(N)n2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N3CCC(c5ccccc5)CC3)CC4)nc(N)n2)CC1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
4-Nitrophenyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 mg, 0.02 mmol) was added to a mixture of 4-phenylpiperidine (4.9 mg, 0.031 mmol) (Aldrich, Cat. #639869) and N,N-diisopropylethylamine (11 uL, 0.061 mmol) in N-methylpyrrolidinone (0.5 mL). The reaction mixture was stirred at 110° C. for 5 h. The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=512.3.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:21]([CH2:26]Br)[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][O:24][C:22]([CH:21]1[CH2:26][N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10][CH2:9][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23]
Reactant: COC(=O)C(Br)CBr
Reactant: c1ccc(CNCCCNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccccc2)CCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
N,N′-Dibenzylpropane-1,3-diamine (Sandstroem, J. et al, Tetrahedron; EN; 34; 1978; 371-378) (2.0 g, 7.86 mmol), methyl 2,3-dibromopropionate (1.28 ml, 7.86 mmol), and potassium carbonate (2.17 g, 15.72 mmol) were dissolved in dry dimethylformamide (125 ml) and methanol (20 ml) and the mixture was heated to reflux for 6 days. The reaction mixture was allowed to cool to room temperature and water (200 ml) and ethyl acetate (200 ml) were added. The aqueous layer was extracted with 2×200 ml of ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered and the solvent was evaporated. The crude product was purified by chromatography on silica, using a mixture of ethyl acetate and heptane 1:6 as the eluent. Fractions containing the product were evaporated, to afford 180 mg of 3A as an clear oil in 7% yield.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[NH:26][C:27](=[O:30])[O:28][CH3:29].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>CC#N>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=2[NH:26][C:27](=[O:30])[O:28][CH3:29])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Nc1cc(Cl)cc(Cl)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccnc1
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (100 mg, 0.33 mmol) and methyl (2-amino-3,5-dichlorophenyl)carbamate prepared in Step 2 (77 mg, 0.33 mmol, 1.0 eq) were mixed with 1 mL of CH3CN. 3-Picoline (0.07 mL, 0.66 mmol, 2.0 eq) was added to the mixture thus obtained, followed by stirring for 30 minutes. After 30 minutes, methanesulfonyl chloride (0.04 mL, 0.5 mmol, 1.5 eq) was slowly added to the mixture. Upon completion of the dropwise addition, the mixture was heated to 40° C. and subjected to a reaction for 24 hours. After confirming the termination of the reaction by using TLC, the solvent was removed, and the residue thus obtained was purified by column chromatography using 20% EtOAc/hexane solution, 50% EtOAc/hexane solution and 100% EtOAc in turn to yield the title compound (130 mg, yield: 75%).
Reaction SMILES: CO[C:3]([C:5]1([CH3:27])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[NH:6]1)=[O:4].[Br:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33]>CC(=O)CC>[Br:28][CH2:29][CH2:30][N:31]1[C:32](=[O:33])[N:6]2[CH:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:27])[C:3]1=[O:4])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=4
Reactant: O=C=NCCBr
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Solvent: CCC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3.17 g (1RS,3SR)-1-(3-Hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 35 ml 2-butanon are added 860 μl bromoethyl isocyanate. The mixture is heated to reflux for 7 h and is stirred at room temperature over night. The precipitated compound is filtered and washed with 2-butanon. 3.09 g (74%) of the title compound are obtained. m.p.: 299-302° C., MS: m/z (MH+)=484.0/486.0
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.Br[CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)C.CN(C)C=O>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:22])([CH3:1])[CH2:3][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:20][CH2:21]2)[CH2:5]1
Reactant: FC(F)(F)CCCBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccccc2N2CCN(CCCC(F)(F)F)CC2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of the 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), 1-bromo-4,4,4-trifluorobutane (24.4 mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2 hours and 30 minutes at an external temperature of 60° C. Aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-(4,4,4-trifluorobutyl)piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C1(P(Cl)([Cl:35])=O)C=CC=CC=1>O>[Cl:35][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Solvent: O
Product: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 150 °C

Procedure:
To 1.0 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2-pyridone was added 1.3 ml (3.37 eq.) of phenylphosphonic dichloride, and the mixture was heated at 150° C. for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 1:2), to give an oily product. Yield: 950 mg (90.5%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[S:14][C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[C:17](=[O:19])[N:18]=3)[CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26]>FC(F)(F)C(O)=O>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[S:14][C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[C:17](=[O:19])[N:18]=3)[CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:24][C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
tert-Butyl [2-oxo-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]-1-imidazolidinyl]acetate (0.31 g, 0.70 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated and the residue was recrystallized from diethyl ether-methanol to give the titled compound (0.22 g, 81%) as white crystals.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>ClCCl>[CH:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][C:10]=1[S:16]([OH:19])(=[O:18])=[O:17]
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc2c(c1)Sc1ccccc1S2
Reaction time: 4 h

Procedure:
To a stirred solution of thianthrene (6.0 g, 27.7 mmol) in 160 mL of dichloromethane at 0° C. was added dropwise, 2.03 mL (30.5 mmol) of chlorosulfonic acid. The resulting deep purple mixture was stirred for 4 hours and then hexanes were added, and the reaction was filtered to give thianthrene-2-sulfonic acid. This acid (3.18 g, 10.7 mmol) was mixed with 7.36 g (35.3 mmol) of phosphorous pentachloride, and the neat solids were heated to a melt at 110° C. for 2 hours. The resulting mixture was quenched with ice and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated to give the title compound as a green oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.Cl[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CN(C)CCCl
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CN(C)CCOc1ccc(C=O)c(Cl)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A suspension of 2-chloro-4-hydroxybenzaldehyde (234 mg, 1.49 mmol), (2-chloroethyl)dimethylamine hydrochloride (536 mg, 3.72 mmol), potassium carbonate (514 mg, 3.72 mmol), and tetrabutylammonium iodide (55 mg, 0.15 mmol) in 4.0 mL of acetonitrile was stirred at 115° C. overnight in a sealed tube. After the reaction mixture was diluted with water, the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 94/6) to obtain the title compound as a brown oil (137 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C@@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]2)=[O:9])=[CH:4][C:3]=1[F:17].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([C@@H:10]2[CH2:14][O:13][C:12]([CH3:15])([CH3:16])[O:11]2)[OH:9])=[CH:4][C:3]=1[F:17]
Reactant: CC1(C)OC[C@@H](C(=O)c2cnc(Cl)c(F)c2)O1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Product: CC1(C)OC[C@@H]([C@@H](O)c2cnc(Cl)c(F)c2)O1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 31 (1.30 g, 5 mmol) in hexanes (30 mL) which was cooled down to −78° C. under N2, L-selectride (20 mL, 10 mmol) was added dropwise. The resulting mixture was further stirred at this temperature for 1 h, and then quenched with brine and diluted with EtOAc (100 mL). The organic layers were washed with brine, dried, and evaporated. The obtained residue was chromatographed on silica gel eluted with EtOAc/hexanes (0-20%) to obtain 0.80 g (31%) of 32 as a yellowish oil. NMR (CD3OD) δ 1.21 (3 H, s), 1.22 (3 H, s), 3.68 (1 H, dd, J=6.36, 8.36 Hz), 3.84 (1 H, dd, J=6.78, 8.52 Hz), 4.00 (1 H, m), 4.23 (1 H, m), 4.70 (1 H, d, J=5.04 Hz), 7.68 (1 H, dd, J=1.52, 9.20 Hz), 8.15 (1 H, d, J=1.96 Hz); LC/MS (M+1) 262.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][NH:17][C:16](=[O:19])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH2:23][CH2:24]N(C)C.C([Li])CCC.C(I)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:23][CH3:24])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 255 mg (0.9 mmol) of 1-tert-butoxycarbonyl-4-(4-methyl-(1H)-pyrazol-3-one-5-yl)piperidine (from Piperidine 15, Step C) and 0.155 mL (1.0 mmol) of freshly distilled tetramethylethylene diamine in 3 mL of THF at −78° C. was treated with 0.8 mL (2.0 mmol) of 2.5 M n-butyl lithium in hexanes (J. Med. Chem. 1996, 39, 3920–3928). After stirring for 15 minutes at −78° C., the reaction was warmed to 0° C. for 15 minutes. Upon recooling to −78° C., 0.11 mL (1.3 mmol) of ethyliodide was added. After warming to rt and stirring for 19 hours, the reaction was cooled to 0° C. and quenched with 1 N HCl. The reaction mixture was partitioned between 100 mL of EtOAc and 100 mL of 1 N HCl. After separating phases, the organic layer washed with 100 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 99:1 v/v CH2Cl2/MeOH, 98:2 v/v CH2Cl2/MeOH and 97:3 v/v CH2Cl2/MeOH as the gradient to afford the title compound as a white solid: RF: 0.40 (19:1 v/v CH2Cl2/MeOH); 1H-NMR (500 MHz) δ 0.73 (t, J=7.4, 3H), 1.26 (s, 3H), 1.47 (s, 9H), 1.59–1.85 (m, 6H), 2.38 (m, 1H), 2.76–2.81 (m, 2H), 4.16–4.21 (m, 2H), 8.61 (br s, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.C(Cl)(Cl)Cl>[C:23]1([CH2:22][C@@H:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20][CH2:21][C@@H:12]2[NH:11][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccccc1C=O
Reactant: NC1CCc2ccccc2C1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccccc1CN[C@H]1CCc2ccccc2[C@H]1Cc1ccccc1
Reaction time: 120 h
Yield: 89.2 %

Procedure:
2-Anisaldehyde (0.22 g, 1.60 mmol) was added to a solution of 2-amino-1-benzyltetralin 10 (0.38 g, 1.60 mmol) and acetic acid (0.096 g, 1.60 mmol) in 1,2-dichloroethane (20 mL) and sodium triacetoxyborohydride (0.51 g, 2.40 mmol) under nitrogen. The resulting suspension was stirred for 5 days and then concentrated in vacuo to provide a yellow film. Saturated aqueous potassium carbonate solution (40 mL) and chloroform (40 mL) were added to this material. The layers were separated, and the aqueous layer was extracted with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated to provide 0.51 g of rac-cis-1-(phenylmethyl)-N-(2-methoxyphenylmethyl)-1,2,3,4-tetrahydro-2-naphthalenamine 11 as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH:10]=[CH:11][C:5]=2[CH:4]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
Here, 1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (1.6 g, 0.0033 mol) is hydrogenated in glacial acetic acid (20 ml) in the presence of 10% palladium/charcoal (50 g) for 6 hours at 50° C. and at pressure (5 bar). The catalyst is removed by suction filtering, the glacial acetic acid is distilled off in vacuo and the residue is neutralized after the addition of water and potssium carbonate. The precipitate is suction filtered, washed with water to remove any salts and dried. The hydrochloride is precipitated from a solution in acetone using ethereal hydrohcloric acid. Yield: 1.2 g. Mp: 236°-238° C.
Reaction SMILES: [O:1]=[C:2]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]([C@H:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[O:12])[CH2:6][CH2:5]2)[O:3]1.[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)C>[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][CH:7]3[CH2:8][CH2:9][C:4]4([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:2](=[O:1])[O:3]4)[CH2:5][CH2:6]3)=[O:12])[CH2:14]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C1OC2(CCC(NC(=O)[C@H]3CCCNC3)CC2)c2ccccc21
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)NC2CCC3(CC2)OC(=O)c2ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of (3S)—N-(3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl)piperidine-3-carboxamide (11 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (6.8 mg, 0.03 mmol), and triethylamine (10.5 μL, 0.075 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 2 hours. The mixture was purified by flash column to yield 10.2 mg of final product was obtained. Yield: 65%. LCMS: 517.0 (M+H)+; 539.1 (M+Na)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][C:10]1[C:11]([C:24](=O)[CH3:25])=[CH:12][C:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[C:18]=2[CH:19]=1)[CH2:7][CH3:8].C([O-])(O)=O.[Na+].[OH-].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O.O.O1CCOCC1.CN(C=O)C>[C:24]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:6][CH2:7][CH3:8])[C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15][C:14]2([CH3:22])[CH3:23])#[CH:25]
Reactant: CCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C#Cc1cc2c(cc1OCCC)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Phosphorous oxychloride (0.234 g, 0.142 mL, 1.52 mmol) was added dropwise to DMF (4 mL) at room temperature under a nitrogen atmosphere. The solution was stirred for 30 min. The 1-(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone, (prepared as described in Example 21, 0.110 g, 0.381 mmol) was added quickly (in one portion) to the orange solution and the reaction solution was heated to 60° C. and stirred for 12 h. The dark brown solution was poured into ice water and the aqueous layer was adjusted to pH 7 with solid NaHCO3. EtOAc extraction afforded the crude product, the chloro enal, 0.128 g, as an orange/brown oil. To a 80° C. solution of NaOH (0.061 g, 1.52 mmol) in dioxane: H2O (3:2; 20 mL) was added the crude chloro enal in a dioxane:water solution (3:2; 5 mL) in one portion and the yellow reaction solution was stirred at 80° C. for 2 h. The resulting orange reaction solution was cooled to room temperature and poured into brine and extracted with EtOAc. The organic solution was dried (MgSO4), filtered, and concentrated to afford an orange oil which was purified by radial chromatography (10:1=Hex:EtOAc) to give the product 6-ethynyl-1,1,4,4-tetramethyl-7-propoxy-1,2,3,4-tetrahydronapthalene 0.040 g (39%) as a yellow oil: 1H-NMR (400 MHz, CDCl3) δ 7.38 (s, 1H, Ar-H), 6.76 (s, 1Hz, Ar-H), 3.98 (t, J=6.6 Hz, 2H, OCH2), 3.19 (s, 1H, CH), 1.83 (m, 2Hz, CH2), 1.66 (m, 2H, 2CH2), 1.26 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3), 0.93 (t, J=7.4 Hz, 3H, CH3).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (174 mg) obtained in Example 6, steps 1-6, (2-fluorophenyl)boronic acid (84 mg), dichlorobis(triphenylphosphine)palladium (18 mg) and potassium carbonate (207 mg) in DME-water (1:1, 5 ml,) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (174 mg, 96%) as a colorless oil.