Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH:37]=O)=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH2:37][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4ccc(CN5CCOCC5)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-{4-[4-amino-7-(5-formylthien-2-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (80.0 mg, 0.149 mmol) and morpholine (51.7 μL, 0.595 mmol) were reacted according to General Procedure B followed by flash chromatography purification to furnish the title compound as a light yellow powder. (1.3 mg, 0.0021 mmol): LCMS (Conditions a): MH−=608.0, RT =4.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.08 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.59 (dd, J=8.5, 0.70 Hz, 1H), 7.34 (m, 1H), 7.31 (m, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.08–7.12 (m, 1H), 7.05 (d, J=3.5 Hz, 1H), 5.69 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 3.72 (s, 2H), 3.61 (t, J=4.5 Hz, 4H), 2.46 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH3:40][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (251 mg) in tetrahydrofuran (3 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (1 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (237 mg, 91%).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[CH:32]1([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:32]1([C:35]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]4[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=4[F:30])[N:15]3[N:14]=2)[CH2:34][CH2:33]1
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Reactant: COC(=O)C#CC1CC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
1.0 g (2.22 mmol) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 7.2 ml of DMF, and 496 mg (4.00 mmol) of methyl 3-cyclopropylprop-2-ynoate were added. 552 mg (4.00 mmol) of potassium carbonate were added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 50 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 384 mg of the title compound were obtained (46% of theory).
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH2:3]1.Cl[O-:15].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(OCC)(=O)C>[O:15]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH2:3]1
Reactant: [O-]Cl
Reactant: NC1CCC(N2CCNC2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C1CCC(N2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 18.3 g of 1-(4-aminocyclohexyl)-2-imidazolidinone as a mixture of cis and trans isomers, 2.0 g of benzyltributylammonium chloride, 250 ml of ethyl acetate and 360 ml of an aqueous 10% potassium hypochlorite solution [according to methodology as described by C. A. Meyers, J. Org. Chem. 26, 1046 (1961)] is stirred at room temperature for 11/2 hours. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The pooled organic phases are washed with water, sodium bicarbonate solution and dilute hydrochloric acid, then dried and evaporated to dryness to yield 1-(4-oxocyclohexyl)-2-imidazolidinone.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[OH-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
1.42 g (0.0048 mol) of L-alanyl-L-proline ethylamide hydrobromide were dissolved in 20 ml of methylene chloride, 21.8 ml (0.01 mol) of 0.5-N sodium hydroxide solution were added followed by 0.54 ml (0.0053 mol) of benzoyl chloride. The mixture was stirred vigorously at room temperature for 1 hour with care being taken that the solution remained basic, this being achieved by the addition of a few drops of 0.5-N sodium hydroxide solution. The layers were then allowed to separate and the methylene chloride layer was separated, dried over magnesium sulphate and evaporated to an oil which crystallised on treatment with ethyl acetate. The crystals were filtered off, washed and dried to yield 1.05 g of N-benzoyl-L-alanyl-L-proline ethylamide of melting point 200°-202° C.; [α]D20 =-82.7° (c=0.99 in methanol).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH2:27][C:26]#[CH:25])[CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=[N+]([O-])O
Solvent: CC(C)=O
Product: C#CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (1.0 g, 3.94 mmol) was dissolved in acetone (100 mL) followed by addition of Cs2CO3 (3.84 g, 11.82 mmol, 3.0 eq) and propargyl bromide (80% in toluene) (463 μL, 4.33 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours. The solution was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (100 mL) and washed with water (100 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 7-nitro-3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (756 mg, 83%). m.p.=122-125° C.; LCMS (m/e) 231 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.05-7.98 (m, 2H), 7.30-7.23 (m, 1H), 3.49-3.43 (m, 2H), 3.13-3.02 (m, 4H), 2.84-2.71 (m, 4H), 2.26-2.22 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH2:13]([NH:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([Cl:17])[C:2]=1[NH:1][C:22](=[O:23])[CH2:21][CH2:20][O:19][CH3:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: COCCC(=O)Cl
Product: CCCCNc1c(NC(=O)CCOC)c(Cl)nc2ccccc12

Procedure:
Using the general method of Example 110, 3-amino-4-butylamino-2-chloroquinoline (10 g, 0.04 mole, Example 113) was reacted with 3-methoxypropionyl chloride to provide 10.3 g of the desired product as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:18])[S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[F:18][CH:2]([F:1])[S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)(=[O:27])=[O:4]
Reactant: Cn1cc(S(=O)C(F)F)c(=O)c2ccc(F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)C(F)F)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a solution of 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (5) (79 mg, 0.287 mmol) in DCM (8 mL) was added ˜80% MCPBA (55.7 mg, 0.258 mmol). The mixture was stirred at a room temperature overnight. An additional amount of MCPBA (15 mg) was added and stirring was continued for 3 days. The mixture was diluted with DCM (10 mL), washed with 5% aqueous Na2CO3 (3×5 mL), the aqueous layers were extracted with DCM (2×10 mL), the combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue, e.g., the crude product, was recrystallized from ethyl acetate to give 27 mg (32%) of white crystals [3-difluoromethyl sulfonyl-7-fluoro-1-methyl-4-quinolone (6)]. The filtrate was chromatographed on silica gel with ethyl acetate-hexane (gradient 1:2, 1:1) to give second crop of the product [3-difluoromethylsulfonyl-7-fluoro-1-methyl-4-quinolone (6)] (32 mg, 38%) for a total yield 70%. This 3-difluoromethylsulfonyl-7-fluoro-1-methyl-4-quinolone gave the following NMR profile:
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)NCCc1cccn1-2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 6,7-dihydro-5H-pyrrolo[1,2-a][l,5]benzodiazepine in 30 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]1([C:13]#[N:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][C:31](Cl)=[O:32])=[C:25]([CH3:34])[CH:24]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH3:34])[C:26]([CH2:30][C:31]([N:4]([C:5]2([C:13]#[N:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]2)[O:3][CH2:1][CH3:2])=[O:32])=[C:27]([CH3:29])[CH:28]=1
Reactant: CCONC1(C#N)CCN(OC)CC1
Reactant: Cc1cc(Cl)cc(C)c1CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCON(C(=O)Cc1c(C)cc(Cl)cc1C)C1(C#N)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-ethoxyamino-1-methoxy-piperidine-4-carbonitrile (2.0 g, 10.04 mmol), triethylamine (3.49 ml, 2.54 g, 25.09 mmol) and a catalytic amount of 4-dimethylamino-pyridine in tetrahydrofuran (10 ml) at 0° C. was added a solution of (4-chloro-2,6-dimethyl-phenyl)-acetyl chloride (2.18 g, 10.04 mmol) in tetrahydrofuran (1 ml) dropwise. The suspension was stirred at 0° C. for 15 minutes, and at room temperature overnight. The reaction mixture was evaporated, diluted with ethyl acetate and water, and the layers separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The crude material was triturated with diisopropyl ether, filtered and the filtrate concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:1). Yield: 1.53 g of 2-(4-chloro-2,6-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-ethoxy-acetamide (title compound P3ii.49) as a colorless oil, which solidified upon standing, mp 100-103° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1F.[F:15]C1C(OC)=C([N+]([O-])=O)C=CC=1CO>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([O:9][CH3:10])[C:8]=1[F:15]
Reactant: COc1c([N+](=O)[O-])ccc(CO)c1F
Reactant: COc1cc(CCl)c(F)cc1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])ccc(CCl)c1F

Procedure:
The title compound was prepared using the procedure from Compound 130C (1-(chloromethyl)-2-fluoro-5-methoxy-4-nitrobenzene) with (2-fluoro-3-methoxy-4-nitrophenyl)methanol (Compound 147D). 1H NMR (CDCl3, 400 MHz): δ=4.10 (d, J=1.77 Hz, 3H), 4.64 (d, J=1.52 Hz, 2H), 7.62 (dd, J=8.59, 1.77 Hz, 1H). MS (ES+): m/z 220.00 [MH+] (TOF, polar).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Cl)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[Na+].[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.Cl>C(#N)C>[Br:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:29]3[CH2:30][CH2:31][CH2:32][CH:28]3[CH3:27])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1CCCN1
Reactant: ClCCCOc1ccc(-c2nc(CN3CCCCC3)c(Br)o2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CN3CCCCC3)c(Br)o2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A solution of 1-[(5-bromo-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl)methyl]piperidine i90 (0.39 g, 0.94 mmol, 1 eq) and 2-metlhylpyrrolidine (192 μl, 1.89 mmol, 2 eq) in acetonitrile (6 ml) is treated with sodium iodide (14 mg, 0.09 mmol, 0.1 eq) and stirred for 24 h at 90° C. 2-Methylpyrrolidine (100 μl, 1 mmol) is then added and the mixture is stirred for a further 24 h at 90° C. The mixture is then poured into 0.1 N hydrochloric acid (10 ml) and extracted with diethyl ether (10 ml). The aqueous phase is then treated with 1 N sodium hydroxide to reach pH 10 and extracted with dichloromethane (3×10 ml). The combined dichloromethane extracts are then dried over magnesium sulfate and concentrated to yield 370 mg of an orange oil which is purified by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96:3.6:0.4) to yield 86 mg of 1-[(5-bromo-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]piperidine 117.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:19]([CH3:20])=[C:18](B2OC(C)(C)C(C)(C)O2)[C:17]([CH3:30])=[N:16]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:12][N:11]([CH3:13])[CH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[C:17]([CH3:30])=[N:16][N:15]([CH3:14])[C:19]=3[CH3:20])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C1CCc2ccc(Br)cc21
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(N(C)C)CC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(Method 3): (6-Bromo-indan-1-yl)-dimethyl-amine (0.82 mmol) was dissolved in DME/H2O 1/1 (10 mL) under argon atmosphere. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.82 mmol), K2CO3 (3.08 mmol), and tetrakis-(triphenylphosphine)palladium (3 mol %, 0.025 mmol) were added and the reaction mixture was stirred at 100° C. for 3 h. Then, a second fraction of 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.41 mmol) was added and the reaction mixture was stirred at 100° C. for 2 h more. The reaction mixture was evaporated to dryness, then dissolved in CHCl3 and filtered through Celite® to give the crude product dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine. The crude was purified by flash column chromatography (CH2Cl2 and MeOH as eluents) by using a CombiFlash Companion™ system to yield the base of the title compound. The obtained product was diluted in ethyl acetate and a solution of hydrogen chloride 2.0 M in diethylether was added. The resulting precipitate was filtered and dried under vacuum to yield the title compound dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine dihydrochloride (75%). MS [MH]+=270.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>C(N(CC)CC)C.[Cu]I.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>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 14271.2 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-benzene (1.53 g, 0.015 mol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2Cl2 (210 mg, 0.2 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 4-nitro-2-(phenylethynyl)aniline (340 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 8.37-8.29 (m, 1H), 8.08-8.00 (m, 1H), 7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 1H), 4.95 (brs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 90.7 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (458.6 mg, 1.60 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (500 mg, 1.76 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (711.3 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 90.8%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1.[CH3:55][NH2:56]>>[CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CN
Product: CNC(=O)C(C)(C)C[C@H]1C[C@H](c2ccc(COC[C@@H](C)COC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](N)=[N:21][C:20]=2[CH:31]=1.C1(C)C=CC=CC=1>CS(C)=O>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:22]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[NH:25][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:31][C:20]=3[N:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: NC1=Nc2cc(Cl)ccc2Nc2ccccc21
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCN[C@@H](Cc3ccccc3)C1)c1ccccc1N2
Yield: 52.3 %

Procedure:
Combine 3-(S)-benzyl-piperazine (800 mg, 4.5 mmol), 8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (424 mg, 1.5 mmol), toluene (8 mL), dimethylsulfoxide (2 mL) and reflux for 3 days. Concentrate and pour into water (50 mL), filtrate the resulting solid, redissolve in dichloromethane (200 mL), wash with water and dry over magnesium sulfate. After concentration, purify by flash chromatography (dichloromethane then gradient of methanol 3–10%) to give (316 mg, 53%) of the title compound as a yellow foam: mp 79–92° C.; 1H NMR (CDCl3): δ 2.59 (dd, 1H), 2.90–2.66 (m, 3H), 3.09–2.94 (m, 3H), 3.85 (bm, 1H), 4.03 (bm, 1H), 4.88 (s, 1H), 6.61 (dd, 1H), 6.79–6.84 (m, 2H), 6.97 (t, 1H), 7.06 (t, 1H), 7.35–7.19 (m, 7H); MS (APCI) m/z (rel intensity) 403.4 (100).