Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:24][N:23]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cc(O)c(-c2ccoc2)cn1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)c(-c3ccoc3)cn1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
An amount of 40.0 mg (0.154 mmole) of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (based on a sample that is 39% pure by weight), is dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 29 mg (0.154 mmole) of 2-aminomethyl-5-furan-3-yl-pyridin-4-ol. All solids dissolved and after the mixture is stirred at room temperature for 2 hours, the solution is evaporated to dryness in vacuo, treated with acetonitrile, filtered and washed several times with fresh acetonitrile and dried to give 41 mg of the title compound as a pink solid (64% yield); mp 215-230° C. dec, MS data ES(+) 418.3
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:32]([C:34]1[C:35]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:36][CH:37]=[CH:38][N:39]=1)#[CH:33].C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:35]1[C:34]([C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)=[N:39][CH:38]=[CH:37][N:36]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1nccnc1CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I43) (140 mg, 0.306 mmol), ethyl 2-(3-ethynylpyrazin-2-yl)acetate (I101) (64 mg, 0.34 mmol), bis(triphenylphosphine)palladium(II) chloride (11 mg, 5 mol %) and DMF (2 mL) were loaded into a microwave tube and degassed with a nitrogen for ten minutes. Copper(I) iodide (3 mg, 5 mol %) and triethylamine (0.192 mL, 1.38 mmol) were added under nitrogen and the resulting mixture heated under microwave irradiation (120° C./15 minutes). The cooled mixture was concentrated, and the residue evaporated onto silica gel. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I102) (95.5 mg, 52% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.47 (s, 1H), 8.87 (d, J=0.5 Hz, 1H), 8.76-8.71 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.15-3.99 (m, 6H), 2.80 (s, 2H), 2.70-2.63 (m, 1H), 1.80-1.70 (m, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.73 min; m/z 633.1 [M+Na]+, 555.0 [M-tBu+2H]+, 511.1 [M-Boc+2H]+; m/z 609.1 [M−H]−.
Reaction SMILES: N[C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[CH2:15][OH:16])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](CO)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A sample of (3R,4S)-tert-butyl 4-amino-3-(hydroxymethyl)piperidine-1-carboxylate (113.6 mMol) was dissolved in CH2Cl2 prior to the addition of saturated sodium carbonate (180 mL). This mixture was cooled to 0° C. and then benzyl chloroformate (21.76 mL, 136.32 mMol) was added slowly. The cooling was removed and stirring continued overnight. Partitioned the mixture between water and CH2Cl2. Aqueous layer was re-extracted with CH2Cl2. Combined organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and dried in vacuo to get the desired product, (3R,4S)-tert-butyl 4-(benzyloxycarbonyl)-3-(hydroxymethyl)piperidine-1-carboxylate as a yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].[CH3:17]I>C(O)C.O>[CH3:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: CI
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cc3ccccc3cc2[nH]1
Yield: 122.3 %

Procedure:
20.0 g of 1H-naphth[2,3-d]imidazole-2-thiol and 4.0 g of sodium hydroxide were heated for 1 hour under reflux and in 150 ml of ethanol with 6.5 g of methyl iodide. The reaction solution was diluted with 500 ml of water and the precipitated product was suction filtered. Crystallisation from dioxane provided 12.0 g of 2-methylthio-1H-naphth[2,3-d]imidazole having a m.p. of 242°-244°.
Reaction SMILES: [C:1]([C:4]([CH3:37])([CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([C:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)([CH3:37])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(C)(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cc2nn3c(C(C)(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 1, 3.08 g (6.07 mmol) of 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-methyl-5-phenylpentanamide and 4.44 mg (29.0 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-1-methyl-4-phenylbutyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one.
Reaction SMILES: C[O-:2].Cl.NO.[CH3:6][C:7]1[CH:8]=[C:9]([C:15]#[N:16])[CH:10]=[N:11][C:12]=1[S:13][CH3:14]>CO>[CH3:6][C:7]1[CH:8]=[C:9]([C:15]([NH2:16])=[O:2])[CH:10]=[N:11][C:12]=1[S:13][CH3:14]
Reactant: C[O-]
Reactant: CSc1ncc(C#N)cc1C
Agent: Cl
Agent: NO
Solvent: CO
Product: CSc1ncc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 168 h
Yield: 74.7 %

Procedure:
To a stirred s odiu m methoxide solution (25 wt % in methanol; 10.53 g, 48.7 mmol) diluted in dry methanol (100 mL) at room temperature under a nitrogen atmosphere was added hydroxylamine hydrochloride (3.38 g, 48.7 mmol) and 5-methyl-6-methylthio-3-pyridinecarbonitrile (2.00 g, 12.2 mmol). The white suspension was stirred at room temperature for 7 days, when it was evaporated in vacuo. The crude white solid was chromatographed on silica gel (25% EtOAc/pentane) yielding the desired product (1.66 g, 75%) as a white fluffy powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[O:37]([CH2:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:23]=[C:22]([C:45](=[O:46])[CH2:44][O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reactant: O=C(Cl)COc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccccc1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reaction time: 2 h

Procedure:
A mixture of N-[2-chloro-4-(tri-n-butylstannyl)benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin (Example 375; 100 mg), phenoxyacetyl chloride (100 μL, 0.72 mmol), tris(dibenzylidene-acetone)dipalladium(0) (18 mg, 0.02 mmol), potassium carbonate (50 mg, 0.36 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) in tetrahydrofuran (2 mL) was shaken for 2 h, then washed with water, dichloromethane, and methanol. Cleavage was effected by treatment with trifluoroacetic acid/dichloromethane (1:1; 4 mL) and shaking for an hour. The cleavage solution was collected by filtration and the solvent was evaporated. The residue was purified by reverse phase HPLC to give N-[2-chloro-4-(phenoxyacetyl)benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:12]([O:10][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])[CH3:13]
Reactant: O=Cc1cccc(F)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1c(F)cccc1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 3-fluoro-2-hydroxybenzaldehyde (5.000 g; 35.70 mmol), iodoethane (11.131 g; 71.40 mmol), and K2CO3 (5.918 g; 42.80 mmol) in anh. DMF (100 ml) was heated to 80° C., under nitrogen, for 3 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-3-fluorobenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.74 min.; no ionisation.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][CH:7]=1
Reactant: Nc1ccc(SCCCCl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(SCCCCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a cooded (5° C.) solution of 1-chloro-3-(4-aminothiophenoxy)propane (4.9 g, 0.024 mol) and pyridine (2.1 g 0.027 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (3.1 g, 0.027 mol). The mixture was stirred at room temperature for 16 hours, washed with 2 N HCl, brine, dried (MgSO4), and concentrated. Recrystallization from EtOH gave 4.0 g (59%) of product as a pink solid m.p. 61°-63° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(CC)C(C)C)(C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (3.2 g, 6.08 mmol) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (1.11 mL, 6.38 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (1.18 g, 6.38 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (2.23 g, 63%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:4][C:3]=1[NH2:16].[CH3:17][O:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:17][O:18][CH2:19][CH2:20][C:21]([NH:16][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:22]
Reactant: COCCC(=O)Cl
Reactant: Cc1ccc(COC2CCCCO2)cc1N
Product: COCCC(=O)Nc1cc(COC2CCCCO2)ccc1C

Procedure:
Analogously to Example 116b, 4.95 g of 2-methyl-5-(tetrahydropyran-2-yloxymethyl)phenylamine and 3.27 g of 3-methoxypropionyl chloride are reacted. The title compound is obtained as a white solid. Rf=0.33 (2:1 EtOAc-heptane); Rt=3.60.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:34]([Cl:49])=[CH:33][N:32]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:49][C:34]1[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[N:36][C:31]([NH:29][C:27]2[CH:26]=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:32][CH:33]=1
Reactant: CCN1CCCOc2cc(N)ccc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21

Procedure:
10-Camphorsulfonic acid (86 mg, 0.37 mmol) was added to 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (65 mg, 0.34 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (110 mg, 0.34 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 30 min). The mixture was conc. and purified by HPLC, conc., neutralized with MP-Carbonate (2.69 mmol/g loading; 0.50 g, 1.345 mmol), filtered and conc. to give N-{(1R,2R)-2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a light green foam, MP: 108-110° C., LCMS: 495 (M+H); 1H-NMR (DMSO): 9.01 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 7.15 (m, 2H), 6.75 (d, 1H, J=8.4 Hz), 6.67 (d, 1H, J=6.3 Hz), 3.98 (m, 2H), 3.79 (m, 1H), 3.32 (m, 1H), 3.12 (m, 2H), 3.06 (m, 2H), 2.90 (s, 3H), 2.14 (m, 1H), 2.02 (m, 1H), 1.90 (m, 2H), 1.69 (m, 2H), 1.32 (m, 4H), 1.10 (t, 3H, J=7.0 Hz).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([N+:24]([O-])=O)[CH:3]=1>C(O)C.C(O)(=O)C.[Fe]>[I:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)=[O:7])=[C:4]([NH2:24])[CH:3]=1
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(I)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 90.4 %

Procedure:
0.26 g (0.000588 mol) of 1-benzyl-piperidin-4-yl 4-iodo-2-nitro-benzoate was dissolved in 3.3 ml of ethanol, diluted with 3.3 ml of acetic acid and treated with 0.123 g (0.0022 mol) of iron powder. The mixture was boiled at reflux for 4 hrs., the solvent was distilled off, the residue was taken up in ethyl acetate, washed with saturated sodium carbonate solution and sodium chloride solution and the organic phase was dried over sodium sulfate. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:4) as the eluent. 0.232 g (95%) of 1-benzyi-piperidin-4-yl 4-iodo-2-amino-benzoate was obtained as a yellow oil. MS: me/e=437 (C19H22IN2O2 +).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:33]=[C:31]([NH:30][C:26]4[CH:25]=[C:24]([OH:23])[CH:29]=[CH:28][CH:27]=4)[N:32]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1cccc(O)c1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3cccc(O)c3)ncc1CC2
Yield: 0.8 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (210 mg, 7.94 mmol), N-(3-hydroxy-phenyl)-guanidine nitrate (170 mg, 7.94 mmol), NaOH (32 mg, 7.94 mmol), and 2-methoxyethanol (2 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (10% MeOH:EtOAc) gave the pure title product as a yellow solid (20 mg, 8%): mp 310° C. (dec). Anal. RP-HPLC: tR 10.3 min (0-60% MeCN, purity 92%). 1H-NMR (DMSO-d6): δ 9.50 (s, 1H, OH/NH), 9.28 (s, 1H, OH/NH), 8.38 (s, 1H, Py-H), 7.37 (t, 1H, J 2.3, Ph-H), 7.27 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.08 (t, 1H, J 8.3, Ph-H), 6.40 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 3.05 (m, 4H, CH2—CH2), 2.78 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.71, 159.05, 158.88, 157.42, 155.97, 155.20, 141.75, 128.81, 127.83, 115.89, 109.69, 108.35, 105.87, 24.72, 23.09, 19.38. MS (ESI+): m/z 311.06 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[CH3:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Cc1cc(N)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccc(C)n(-c3ccc(F)cc3)c2=O)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Yield: 73.5 %

Procedure:
Using N-[6-(4-amino-2-methylphenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (99.7 mg, 0.403 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (107 μL, 0.620 mmol) and HATU (153 mg, 0.403 mmol) and in the same manner as in Example 57, the title compound (125.7 mg, 74%) was obtained as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][C:8]1[C:9]([CH2:23][CH3:24])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]=1[CH2:13][CH3:14])(C)(C)C.[C:26](=[O:29])([O-:28])N>>[CH2:15]([O:28][C:26]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:11]2[C:12]([CH2:13][CH3:14])=[C:8]([CH2:7][C:6]([OH:5])=[O:25])[C:9]([CH2:23][CH3:24])=[N:10]2)=[CH:21][CH:20]=1)=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)[O-]
Reactant: CCc1nn(Cc2ccc(N)cc2)c(CC)c1CC(=O)OC(C)(C)C
Product: CCc1nn(Cc2ccc(NC(=O)OCc3ccccc3)cc2)c(CC)c1CC(=O)O

Procedure:
Example 3.3 was prepared according to the method described for method 3.1, employing intermediate 2.1.2 instead of intermediate 1.1.3 in the carbamate formation step. The subsequent cleavage of the tert-butyl ester was performed under acidic conditions as described for example 2.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH2:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.ClC(Cl)Cl.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([NH:15][C:26](=[O:34])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(N)CC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(NC(=O)Oc3ccccc3)CC2)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred solution of 8 parts of 4-(4-methoxyphenyl)-1-piperazinamine in 5 parts of pyridine and 45 parts of trichloromethane are added dropwise during a 30 minutes period 7.8 parts of phenyl carbonochloridate. Upon completion, stirring is continued for 30 minutes at room temperature. Water is added to the reaction mixture and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 9 parts (70%) of phenyl [4-(4-methoxyphenyl)-1-piperazinyl]carbamate.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH2:33][CH3:34])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCC)C2)oc1CC
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1CC
Yield: 104.9 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (115a) (1.21 g, 2.5 mmol), 10% Pd/C (0.25 g) and methanol (15 mL), to obtain 0.89 g of the title compound as a light brown oily substance (97%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](OCC)=[O:24].[H-].[Na+].O>CS(C)=O>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:23](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: CCOC(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of 2-(o-aminophenethyl)-1-methylpiperidine (8.0 g., 0.037 mole) and ethyl picolinate (5.5 g., 0.037 mole) in DMSO (20 ml.) is treated with NaH (57%) in oil (1.6 g., 0.037 mole) with intermittent cooling to moderate the resulting vigorous reaction. After 2 hr., the mixture is poured into 150 ml. of H2O and the product isolated according to the procedure of Example 25. Crystallization from isopropyl ether affords 5.9 (50%) of analytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]picolinanilide, m.p. 65.5°-67° C. (corr.).