Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C(OC(=O)[NH:9][C@@H:10]1[CH2:15][CH2:14][C@@H:13]([CH2:16]O)[O:12][CH2:11]1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.II.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.C([O-])([O-])=O.[K+].[K+].[ClH:56]>C(Cl)Cl.CC(=O)OCC.CC(C)=O.CO>[ClH:56].[N:45]1([CH2:16][C@H:13]2[O:12][CH2:11][C@H:10]([NH2:9])[CH2:15][CH2:14]2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CO)OC1
Reactant: C1CCNC1
Agent: Cl
Agent: II
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CO
Product: N[C@@H]1CC[C@@H](CN2CCCC2)OC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of (3R,6S)-6-hydroxymethyl-tetrahydro-2H-pyran-3-yl carbamic acid tert-butyl ester (328 mg, 1.40 mmol, H. S. Overkleeft et al. Eur. J. Org. Chem. 2003, 2418), triphenylphoshine on polystyrene (6.16 mmol) and imidazole (203 mg, 2.95 mmol) in dry CH2Cl2 (14 mL) was added iodine (891 mg, 3.48 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, CH2Cl2 removed under reduced pressure. The residue was redissolved in EA, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by FC, the iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (1.13 mL, 13.57 mmol) and K2CO3 (750 mg, 5.43 mmol). The reaction mixture was stirred at 85° C. until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1) and then the Boc group was removed by treatment with HCl (4.0 M in dioxane, 9 eq.) in dry CH2Cl2 (2 mL). The title compound was obtained after trituration in hot EA/acetone/MeOH as an off-white solid. LC-MS-conditions 01: tR=0.15 min; [M+H]+=185.06.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1)([CH3:3])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(C(C)C)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(C)C)ccc1C(C)=O

Procedure:
4′-isopropyl-2′-hydroxyacetophenone (33.4 g, 187.4 mmol) is dissolved in acetone (233 ml). Following addition of K2CO3 (51.8 g, 374.8 mmol) and methyl iodide (23.33 ml, 374.8 mmol) the batch is heated at reflux for three days. The reaction mixture is cooled and filtered through a glass fibre filter and the residue is washed with cold acetone. The solvent is removed and the residue is chromatographed (silica gel, eluent: ethyl acetate/hexane). This isolates 31.85 g (88.4%) of the desired compound.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C@@:15]([CH2:20][CH:21]([CH2:23][OH:24])[OH:22])([C@H:16]([CH2:18][OH:19])[OH:17])[O:14][C:12](=[O:13])[C:11]=1[OH:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])O.[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>CS(C)=O>[CH2:1]([O:9][C:10]1[C@@:15]([CH2:20][CH:21]([CH2:23][OH:24])[OH:22])([C@H:16]([CH2:18][OH:19])[OH:17])[O:14][C:12](=[O:13])[C:11]=1[O:25][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCCCCCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOC1=C(OCCCCCCCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
Under an argon atmosphere, 3-O-octylglyceryl ascorbic acid (5.17 g) obtained in Example 8 was stirred in DMSO (10 mL), and further, sodium hydrogen carbonate (1.20 g) and hexadecyl bromide (5.22 g) were added. The mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 9.06 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:50/310.3), and concentration was performed under reduced pressure to obtain 3-O-octylglyceryl-2-O-hexadecyl ascorbic acid (3.41 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>ClC(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)N1CCCC1
Reaction time: 6 h
Yield: 40.1 %

Procedure:
To a stirred solution of 7.5 parts of 2-(methylamino)ethanol in 75 parts of trichloromethane were added 9.8 parts of N,N-diethylethanamine while cooling in an ice bath. A solution of 13.4 parts of 1-pyrrolidinecarbonyl chloride in 52.5 parts of trichloromethane was added dropwise (exothermic reaction, the temperature rose from -10° C. to ~0° C.). Upon complete addition, stirring was continued for 6 hours at room temperature. Another portion of 1.5 parts of 2-(methylamino)ethanol was added and stirring was continued over weekend at room temperature. The separated organic layer was washed with a hydrochloric acid solution 5% and water, dried, filtered and evaporated, yielding 7 parts (40.1%) of N-(2-hydroxyethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 30).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[Br:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=[NH:18])[NH:14][CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1>>[Br:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13]3[N:14]([CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:18]=3)[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: O=C(O)C(=O)CBr
Reactant: N=C1NCCOc2cc(Br)ccc21
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2

Procedure:
Reaction of 3-bromo-2-oxopropanoic acid and 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 33 gives 28 (CAS Reg. No. 1282516-74-8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH:25][C:26]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:37].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][N:25]([CH3:37])[C:26]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CCOCC4)c3)cnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1)C(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
6-(5-{[(Tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (132 mg, 0.29 mmol) is dissolved in DMF (4.0 mL) and cooled down to 0° C. Sodium hydride 60% in mineral oil (14 mg, 0.35 mmol) is added and the mixture is stirred for 10 min. Then iodomethane (0.036 mL, 0.58 mmol) is added and the reaction mixture is warmed up to room temperature for 2 hrs. Saturated NH4Cl aqueous solution (2.0 mL) is added along with water (10 mL) and EtOAc (15 mL). The mixture is stirred for 10 min, the aqueous layer is separated and extracted with EtOAc (2×10 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 70 mg of 6-(5-{[methyl-(tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH3:5][O:6][C:7](=[O:19])[C:8](N=NC(C)(C)C(O)=O)([CH3:10])[CH3:9]>>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH3:5][O:6][C:7](=[O:19])[C:3]([CH3:2])([CH3:4])[C:8]([CH3:9])([CH3:10])[C:7]([O:6][CH3:5])=[O:19]
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)O
Agent: C=CC=C
Product: COC(=O)C(C)(C)C(C)(C)C(=O)OC
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Preparation of the polybutadiene dicarboxylic acid dimethyl ester used in Examples 1 to 6 and in Comparison Examples II and III is carried out by the bulk polymerisation of butadiene, for which purpose 325 g of 1,3-butadiene are added under nitrogen to quantities of 55 g, 39 g, 21 g and 7 g of azo-bis-isobutyric acid methyl ester. The reaction mixture is stirred for 14 to 16 hours at 80° C., the polymerisation reaction taking place under the natural pressure of the system (around 12 bars). Thereafter the excess butadiene is distilled off. Residual butadiene and tetramethyl succinic acid dimethyl ester, formed as a secondary product, are removed over a period of 6 hours at 0.1 mbar in a rotary evaporator (bath temperature 90° C.), leaving 174 g, 140 g, 95 g and 40 g, respectively, of a crystal-clear liquid having an Mn of 800 (as determined by vapour pressure osmosis) and containing 78 mole percent of 1,4-bonds; Mn 1000 and containing 79 mole percent of 1,4-bonds; Mn 1300 and containing 80 mole percent of 1,4-bonds; Mn 6000 and containing 82 mole percent of 1,4-bonds.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(O)(C(F)(F)F)=O.C(#N)C>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[N:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=Cc1cccc(F)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(N=Cc2cccc(F)c2)cc1

Procedure:
The reaction of 4-fluoroaniline and 3-fluorobenzaldehyde in TFA and acetonitrile provided the N-3-fluorobenzylidene-4-fluoroaniline. The cyclopentadiene was separately prepared from its dimer dicyclopentadiene. The dimer was heated at 180° C. to give monomer, which was reacted with N-3-fluorobenzylidene-4-fluoroaniline in acetonitrile in presence of TFA to provide the desired difluoro compound 100.
Reaction SMILES: [OH-].[Na+].CS([C@@:7]1([OH:32])[C@:11](S(C)(=O)=O)(O)[C@@H:10]([CH:17]([S:19]([CH3:22])(=[O:21])=[O:20])[OH:18])[O:9][C@H:8]1[N:23]1[CH:30]=[C:29]([CH3:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])(=O)=O.Cl>>[CH3:22][S:19]([CH:17]([OH:18])[C@H:10]1[O:9][C@@H:8]([N:23]2[CH:30]=[C:29]([CH3:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:7]2[O:32][C@H:11]12)(=[O:20])=[O:21]
Reactant: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@](O)(S(C)(=O)=O)[C@]2(O)S(C)(=O)=O)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@H]3O[C@H]32)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 49 ml 1N sodium hydroxide was added 2',3',5'-tris(methanesulfonyl)-5-methyluridine (2, 6.0 g). The mixture was stirred at 70°-72° C. for 15 minutes and then cooled 0° C. The pH was adjusted to 4 by using concentrated HCl. The resulting slurry was filtered, washed with 2×10 ml water and dried to give 5'-methanesulfonyl-2'-3'-anhydro-5-methyluridine (3), 3.1 g, (84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1.C[Si]([C:40]#[CH:41])(C)C>N1CCCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:26]2[C:27]([CH3:28])=[C:23]([C:21]([NH:20][C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:13][CH2:12][CH:11]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH2:10][CH2:9]4)=[C:2]([C:40]#[CH:41])[CH:3]=3)=[O:22])[CH:24]=[N:25]2)=[CH:30][CH:31]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Br)c2)cnn1-c1ccc(Cl)cc1
Solvent: C1CCNCC1
Product: C#Cc1cc(NC(=O)c2cnn(-c3ccc(Cl)cc3)c2C)ccc1N1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
A suspension of N-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide (1 g), bistriphenylphosphinepalladium dichloride (0.38 g), cuprous iodide (0.06 g), trimethylsilylacetylene (0.53 g) and piperidine (50 ml) was refluxed under heating for 15 h. The solvent was evaporated and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane). The resulting residue was dissolved in methanol (10 ml) and potassium carbonate (170 mg) was added. The mixture was stirred at room temperature for 1 h. After the reaction, potassium carbonate was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: chloroform/methanol) and recrystallized from a mixed solvent of chloroform-diisopropyl ether to give the title compound (27 mg), melting point: 203–205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:15])[NH:13][CH3:14])[CH:9]=[C:8]([Cl:16])[C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:15])[NH:13][CH3:14])[CH:9]=[C:8]([Cl:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1

Procedure:
A well stirred mixture of methyl 2,6-dichloro-4-(methylcarbamoyl)benzoate (280 mg, 1 mmol, Step a) and anhydrous lithium iodide (429 mg, 3.2 mmol) in pyridine (3 mL) was heated under reflux for 3 hours. The reaction mixture was concentrated under vacuum to remove pyridine. The residue was acidified using ice-cooled dilute hydrochloric acid solution and partitioned with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum to obtain a solid that upon triturating with cold diethyl ether yielded pure 2,6-dichloro-4-(methylcarbamoyl)benzoic acid (200 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.B.[C:16]([C:19]1[CH:20]=[C:21](CC(C(O)(C)C)(C)O)[C:22]([CH3:25])=[CH:23][CH:24]=1)([OH:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([CH2:9][NH:8][C:6]([C:5]2[CH:13]=[CH:14][C:2]([C:23]3[C:22]([CH3:25])=[CH:21][CH:20]=[C:19]([C:16]([OH:18])=[O:17])[CH:24]=3)=[CH:3][CH:4]=2)=[O:7])[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Br)cc1
Reactant: Cc1ccc(C(=O)O)cc1CC(C)(O)C(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(C(=O)O)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 78 %

Procedure:
4-Bromo-N-cyclopropylmethylbenzamide (2.0 g, 7.87 mmol), (3-carboxy-6-methylphenyl) pinacol borane (2.06 g, 7.87 mmol), tetrakis(triphenylphosphine)palladium (900 mg, 0.79 mmol) and aqueous sodium carbonate (1M, 50 ml) in DME (100 ml) were heated at 90° C. for 18 h. The organic phase was absorbed onto silica and purified by flash chromatography (silica) eluting with DCM/ethanol/ammonia (20:8:1) to give {4′-[(cyclopropylmethylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}carboxylic acid (1.9 g, 78%). LCMS: retention time 3.18 min, MH+310.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:16])[CH2:12][C:13]([O-:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:28][CH:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]([CH3:16])[CH2:12][C:13]([NH:28][CH:29]1[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CN(CC(=O)[O-])C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(CC(=O)NC1CN(C(=O)OC(C)(C)C)C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(((benzyloxy)carbonyl)(methyl)amino)acetate (2.12 g, 9.50 mmol, prepared the previous step) and EDCI (1.99 g, 10.4 mmol) were stirred in anhydrous DCM (10 mL) for 15 minutes and then added to a solution of commercially available tert-butyl 3-aminoazetidine-1-carboxylate (1.64 g, 9.52 mmol) and DMAP (220 mg, 1.80 mmol) in DCM (90 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated ammonium chloride solution, 1 N NaOH solution, brine and the organic layer dried over Na2SO4. After concentration in vacuo, the residue was purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a white solid after drying under high vacuum.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:28]C)=[CH:10][C:11]([O:26]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[I:24])=[CH:14][C:13]3=[O:25])[CH2:6][CH2:5][N:4]1[CH3:30].Cl.N1C=CC=CC=1>>[OH:26][C:11]1[CH:10]=[C:9]([OH:28])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:30])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:25])[CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[I:24])[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3I)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4I)oc23)[C@@H]1CO

Procedure:
Compound of example 18 (0.29 g, 0.588 mmol) subjected to demethylation using pyridine hydrochloride (3 g, 25.97 mmol) as described in example 17, afforded the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([C:15]([CH3:27])=[N:16][C:17]=2[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:13]=1[OH:14]>C1(C)C=CC=CC=1>[Cl:3][CH2:6][CH2:7][C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([C:15]([CH3:27])=[N:16][C:17]=2[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:13]=1[OH:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCO)c(C)nc23)c(C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCCl)c(C)nc23)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Thionyl chloride (112 mL, 1.54 mmol) was added to a solution of 3-(2-hydroxyethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidin-4-ol (500 mg, 1.54 mmol) in toluene (5 mL) at 80° C., followed by stirring for one hour. After cooling to room temperature, the resulting crystals were washed with diethyl ether, to give the title compound (360 mg) as pale brown crystals.
Reaction SMILES: CN(C)C=O.FC(F)(F)S(O[C:12]1[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=O)=O.[C:29]([C:31]1([OH:39])[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1)#[CH:30].C(N(CC)CC)C>C(Cl)(Cl)Cl.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]1([CH2:20][CH2:19][C:13]2[C:12]([C:30]#[C:29][C:31]3([OH:39])[CH:36]4[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]4)[CH2:32]3)=[CH:17][CH:16]=[C:15]([CH3:18])[N:14]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CCc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C#CC2(O)CN3CCC2CC3)c(CCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
10 ml of N,N-dimethylformamide was added to a mixture of 1.2 g of 6-methyl-2-(2-phenylethyl)pyridyl trifluoromethane sulfonate, 522 mg of 3-ethynyl-3-quinuclidinol, 400 mg of tetrakis(triphenylphosphine)palladium(0), 217 mg of cuprous iodide and 1.7 ml of triethylamine, followed by heating under stirring at 50° C. in an oil bath for one hour in a nitrogen atmosphere. After cooling as it was, the reaction solution was sprinkled over silica gel and subjected to silica gel column chromatography using chloroform/methanol/aqueous 36% ammonia (46:5:0.5) as an eluent for separation and purification, to give 490 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1B(O)O.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=2)[CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[C:35]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:34]=[CH:33][N:32]=2)[CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(F)c1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 71.8 %

Procedure:
To a solution of 2-fluoro-6-methoxyphenyl boronic acid (0.20 g, 1.1 mmol) in a mixture of THF and water (6 ml, 1:1), 3-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (0.35 g, 0.93 mmol) was added at 0° C. followed by palladium acetate (12 mg, 54 μmol), PPh3 (31 mg, 0.12 mmol) and saturated solution of sodium carbonate (2 ml). The reaction mixture was stirred at room temperature for 30 h and then filtered through a celite bed which was washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried and evaporated under reduced pressure. The crude product was purified by column chromatography, using hexane/ethyl acetate (4:1) as eluent, to provide 0.31 g (yield: 66.7%) of 3-[6-(2-fluoro-6-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][CH:13]=O.C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:11][C:5]1[CH:4]=[C:3]([CH2:12][CH2:13][N:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)[C:2]([Cl:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: O=CCc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2cc(Cl)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A methylene chloride solution of the title compound of Example 10 was stirred at room temperature under nitrogen. Acetic acid (8.8 ml, 153 mmol) was added in one portion followed by t-butylpiperazinecarboxylate (8.4 g, 50 mmol). Sodium triacetoxy-borohydride (16.2 g, 77 mmol) was added in portions as a solid and the reaction mixture stirred at room temperature for three hours. The reaction mixture was washed two times with excess saturated sodium carbonate solution and one time each with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title product as an oil 15.6 g, (98% crude yield). This was suitable for use in the next reaction without further purification. NMR (CDCl3) δ 7.92 (s, 1), 7.48 (s, 1), 3.43 (m, 4), 2.97 (t, 2), 2.62 (t, 2), 2.49 (m, 4), 1.43 (s, 9).