Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[OH-].[K+].[CH3:25]I>CC(C)=O>[CH3:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3ccccc3[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The tert-butyl 4-(1H-benzimidazol-2-yl)piperidine-1-carboxylate (50.0 mg, 0.166 mmol) was dissolved in 2 mL of acetone with freshly ground potassium hydroxide (46.4 mg, 0.830 mmol). The mixture was stirred for 10 minutes at ambient temperature, and then methyl iodide (11.4 μL, 0.183 mmol) was added. After 10 minutes, the reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL). The sample was diluted with EtOAc (3×30 mL), washed with water (2×20 mL), and washed with brine (2×20 mL). The organic layer was dried over sodium sulfate, filtered, concentrated to give tert-butyl 4-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and benzyl bromide (52 μL, 0.44 mmol) in N,N-dimethylformamide (4.5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-benzyl-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (71.5 mg, 55%) as an off-white solid. APCI-MS (M+H) 297.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][C@@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][C@@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(O)C(=O)OC(C)C
Yield: 50.2 %

Procedure:
To a solution of 61 mg of N-benzyloxycarbonyl-L-alanine and 79 mg of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in 5 ml of N,N-dimethylformamide were added successively 0.071 ml of diphenylphosphoryl azide and 0.125 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform/methanol=20/1 by volume) to obtain 56 mg of isopropyl (2RS, 3S)-3-(N-benzyloxycarbonyl-L-alanyl)amino-2-hydroxy-5-methylhexanoate as a colorless viscous oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:4][CH2:3]1
Reactant: CC1CCN(CC[C@H]2CCCN2C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCN(CC[C@H]2CCCN2)CC1
Yield: 101.9 %

Procedure:
A solution of the protected amine, (R)-2-[2-(4-methyl-piperidin-1-yl)ethyl ]pyrrolidine-1-carboxylic acid, tert-butyl ester (D5) (3.0 g, 10 mmol) in trifluoroacetic acid (15 ml) and dichloromethane (50 ml) was heated to reflux for 18 hours. The reaction mixture was concentrated and the residue partitioned between CH2Cl2 and sat. aqueous K2CO3. The organic phase was dried and concentrated to afford the title compound (2.0 g, q) MH+ 197.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:8]=1[NH:16][C:17](=[O:38])[CH2:18][N:19]1[C:23](=[O:24])[C:22]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:21]([C:30]2[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=2)[C:20]1=[O:37])([CH3:6])[CH3:5]>O1CCCC1.C(OCC)(=O)C.[Cu](I)I.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:1]([C:33]1[CH:34]=[CH:35][C:30]([N:21]2[C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:23](=[O:24])[N:19]([CH2:18][C:17]([NH:16][C:8]3[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=3[CH:4]([CH3:6])[CH3:5])=[O:38])[C:20]2=[O:37])=[CH:31][CH:32]=1)#[N:2]
Reactant: [C-]#N
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(I)cc2)C2(CCCCC2)C1=O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(C#N)cc2)C2(CCCCC2)C1=O
Temperature: 80 °C

Procedure:
38 mg (0.58 mmol, 2 eq.) of potassium cyanide and 5.5 mg (0.029 mmol, 0.1 eq.) of copper iodide are added to 170 mg (0.29 mmol, 1 eq.) of N-(2,6-diisopropyl-phenyl)-2-[1-(4-iodo-phenyl)-2,4-dioxo-1,3-diaza-spiro[4.5]dec-3-yl]acetamide in 10 ml of tetrahydrofuran. The reaction medium is degassed with nitrogen for 20 minutes, and 17 mg (0.015 μmol, 0.05 eq.) of tetrakis(triphenylphosphine)palladium are added. The medium is heated at 80° C. for 6 hours. The medium is cooled to room temperature and diluted with ethyl acetate, and then filtered through Celite. The filtrate is washed with water. The organic phases are combined. They are dried over sodium sulfate. The solvents are evaporated off and the residue is precipitated from dichloromethane and heptane. The product 2-[1-(4-cyanophenyl)-2,4-dioxo-1,3-diaza-spiro[4.5]dec-3-yl]-N-(2,6-diisopropylphenyl)acetamide is obtained in the form of a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:10]([CH2:21][CH2:22][OH:23])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[OH:23][CH2:22][CH2:21][CH:10]1[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: Cc1ccccc1N1CCN(Cc2ccccc2)CC1CCO
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1N1CCNCC1CCO
Yield: 97 %

Procedure:
1-Benzyl-3-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (1.5 g; 4.8 mmol) in 50 mL of MeOH containing 150 mg of palladium black was shaken on a Parr apparatus under an atmosphere of hydrogen (55 psig) for 18 h. The catalyst was removed by filtration through Celite and the filtercake was washed with MeOH. The filtrate solvents were evaporated under reduced pressure to give the title compound as an oil (1H-NMR: consistent with structure; FABMS: M+H @ m/e=221; HPLC: 97%, retention time 5.20 min).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.O.[OH-].[Al+3:17].[OH-].[OH-]>CC(C)=O>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([O-:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8].[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([O-:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8].[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([O-:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8].[Al+3:17]
Reactant: CCOP(=O)(CCC(=O)O)OCC
Agent: [Al+3]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCOP(=O)(CCC(=O)[O-])OCC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Use as a reaction vessel a 500 milliliter (mL) single neck round bottomed flask fitted with a condenser with a nitrogen inlet. Charge the vessel with 3-(diethyoxyphosphoryl)propanoic acid (20.30 g) followed by the addition of water (150 mL) and aluminum hydroxide monohydrate (2.709 g). Heat the resulting solution to 90° C. and hold at that temperature for eight hours. Remove the water using a rotovap to leave behind a solid material. Add 100 mL of acetone and isolate the solid by vacuum filtration using a Buchner funnel and wash with acetone (100 mL). Transfer the solid product to a glass bottle and place in a vacuum oven to dry overnight. The yield of the solid product, aluminum tris(3-(diethoxyphosphoryl)propanoate), is 12.45 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:12][S:13]([CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:7]([OH:9])=[O:8])(=[O:15])=[O:14]
Reactant: NCCCCCC(=O)O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)C(CCCCN)C(=O)O

Procedure:
Analogously to Example 20a, 65.6 g of ε-aminocaproic acid are reacted with 40 ml of methanesulfonyl chloride in the presence of 2N NaOH and the mixture is worked up. The DCA salt is prepared, and 42.3 g of melting point 134° are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:23]=[O:24])=[CH:11][N:10]=1)([CH3:3])[CH3:2].[Se](=O)=[O:29]>C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:23]=[O:24])=[CH:11][N:10]=1)=[O:29])([CH3:3])[CH3:2]
Reactant: COc1cc2c(C=O)cnc(Cc3cccc(OC(C)C)c3)c2cc1OC
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: COc1cc2c(C=O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Yield: 77.1 %

Procedure:
A solution of 1-(3-isopropoxy-benzyl)-6,7-dimethoxy-isoquinoline-4-carbaldehyde (200 mg, 0.547 mmol) and selenium dioxide (121 mg, 1.09 mmol) in ethyl acetate was refluxed for 45 min. The mixture was cooled and filtered through celite. The celite was washed well with ethyl acetate and the combined filtrates were concentrated in vacuo to afford 1-(3-isopropoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbaldehyde (160 mg, 77%) as a light yellow solid that was used without further purification: APCI-MS (M+H+) m/e 380; 1H NMR (300 MHz) compatible.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCc1ccccn1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1ccccn1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 2-(2-aminoethyl)pyridine (65 mg, 0.49 mmol). The title compound was obtained as a solid (55 mg, 30% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.94 (1H, m), 8.49 (2H, m), 8.38 (1H, s), 7.69 (1H, m), 7.23 (1H, m), 3.56 (2H, m), 2.96 (2H, m). MS m/z: 453.02, 455.01 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.[CH3:24]OCCO>>[NH2:23][C:13]1[N:14]=[C:15]([O:18][C@@H:19]2[CH2:24][CH2:22][O:21][CH2:20]2)[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COCCOc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: COCCO
Product: Nc1nc(O[C@@H]2CCOC2)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
6-(4-fluoro-phenyl)-4-(2-methoxy-ethoxy)-pyrido[3,2-d]pyrimidin-2-ylamine (example 23) was obtained from 2-methoxy-ethanol; MS (m/z): 315 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([OH:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[CH2:30]1.O>CN(C=O)C>[CH3:34][C:31]1([CH3:35])[O:32][CH2:33][CH:29]([CH2:28][O:20][C:19]2[C:10]([C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[F:1])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:30]1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(O)c1
Reactant: CC1(C)CC(CBr)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC2COC(C)(C)C2)c1
Yield: 99.7 %

Procedure:
A solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-hydroxynicotinate (700 mg), potassium carbonate (1.10 g) and 4-(bromomethyl)-2,2-dimethyltetrahydrofuran (730 mg) in DMF (5.0 mL) was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (980 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C[Al](C)C>C1COCC1>[OH:42][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@:3]3([C:11]4[CH2:12][C:13]5[C:18]([CH:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[OH:1])=[CH:31][CH:30]=2)=[CH:41][C:37]=1[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Yield: 30.2 %

Procedure:
To a mixture of ethyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (11, 200 mg, 0.48 mmol), 5-amino-2-hydroxybenzoic acid (75 mg, 0.48 mmol) and THF (1.0 mL) in a 5 mL microwave vial, was added trimethylaluminium (0.5 mL, 20% solution in toluene) and the mixture irradiated at 100° C. for 5 min. The reaction mixture was quenched with slow addition of 1.5 N HCl (2 mL) and extracted with ethyl acetate (3×15 mL). Organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue purified by preparative HPLC [Kromasil C18 (250×50 mm), flow rate: 40 mL/min, 0.1% TFA in water/MeOH, run time: 40 min] to yield 75 mg (30%) of the title compound as an off white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[O:23])[C:14](=[C:20]([CH3:22])[CH3:21])[O:15]3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:45]=[CH:44][C:34]([C:35]([NH:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:36])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:45]=[CH:44][C:34]([C:35]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]4[CH:19]=[CH:18][CH:17]=[C:16]5[C:12]=4[C:13](=[O:23])[C:14](=[C:20]([CH3:22])[CH3:21])[O:15]5)=[CH:5][CH:4]=3)[CH2:40][CH2:39]2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: CC(C)=C1Oc2cccc(OCc3ccc(CCl)cc3)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=C1Oc2cccc(OCc3ccc(CN4CCC(NC(=O)c5ccc(F)cc5)CC4)cc3)c2C1=O
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of 570 mg 4-(4-chloromethyl-phenylmethoxy)-2-isopropylidenecoumaran-3-one (preparation 2), 240 mg potassium carbonate, 400 mg 4-(4-fluorobenzamido)piperidine and 15 ml dimethylformamide is warmed to 60° C. for 3 hours, then evaporated, mixed with water and extracted with ethyl acetate. After evaporation of the extract, the residue (0.6 g) is purified by silica gel chromatography (eluent ethyl acetate) to give 180 mg (19%) of the desired compound, m.p. 205-208° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[N:17][C:18]=1Cl>CS(C)=O>[C:20]([C:15]1[CH:14]=[C:13]([Cl:12])[C:18]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[N:17][CH:16]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ncc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 32.2 %

Procedure:
Dimethyl malonate (4.69 g, 35.5 mmol) was dissolved in DMSO (24.0 ml). This solution was added 70% NaH (1.33 g, 33.2 mmol) at 0° C. The resulting mixture was warmed up to room temperature, then stirred at the same temperature for 40 min. To this solution was added 1-(5,6-dichloropyridin-3-yl)ethanone (Tetrahedron 1992, 48, 9233-9236, 4.50 g, 23.7 mmol) at room temperature, then the resulting mixture was stirred at 100° C. for 4 hours. The mixture was partitioned between Et2O and water. The organic layer was washed with water and brine, dried over Na2SO4, then concentrated to give a brown syrup. The crude material was purified by SiO2 column chromatography (100 g, EtOAc/hexane (1/2)) to give the title compound (2.18 g, 32%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.64 (3H, s), 3.83 (6H, s), 5.31 (1H, s), 8.26 (1H, s), 9.02 (1H, s).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a solution of 4-benzylphenol (103 mg, 0.56 mmol) in DMF (1 mL) was added 95% NaH (19 mg, 0.75 mmol) at 0° C., and the resulting mixture was stirred at 0° C. for 10 min. A solution of the tosylate (200 mg, 0.56 mmol) from Step 1 in DMF (2 mL) was added to the reaction mixture dropwise over 5 min., and the reaction was heated at 95° C. for 10 h. The mixture was concentrated and water was added, and extracted with EtOAc. The organic layer was washed with saturated aq. NaHCO3 followed by water and brine. Organic layer was dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude product, which was purified by silica gel flash chromatography to obtain the title product (150 mg, 73%) as a solid: MS; m/z 368 (M+H); 1H NMR (400 MHz, CDCl3); δ 1.46 (m, 9H), 1.84-2.03 (m, 4H), 3.39 (m, 2H), 3.73-3.93 (m, 3H), 4.10 (m, 2H), 6.84 (m, 2H), 7.08 (m, 2H), 7.17 (m, 2H), 7.26 (m, 3H): HPLC (UV), 99.8%.
Reaction SMILES: C(O[C:4]([C:6]1([C:29]([O:31]CC)=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>C(O)C>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][N:40]([CH2:39][C:35]1[O:34][CH:38]=[CH:37][CH:36]=1)[C:4]([C:6]1([C:29]([OH:31])=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5]
Reactant: NCc1ccco1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Solvent: CCO
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)N(Cc1ccco1)Cc1ccco1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and 2-furanylmethylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:methanol to yield a brown solid; mp 50; yield 400 mg; 14%; M+H 581.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([OH:30])[CH3:29])[CH:9]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:30][CH:28]([C:10]1[CH:9]=[C:8]([N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:39])([CH3:1])[CH3:40])[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=1)[CH3:29])(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol (6.1 g, 10.4 mmol) in methylene chloride (100 mL) and triethylamine (7.1 mL, 50.9 mmol) under nitrogen was added methanesulfonyl chloride (2.4 mL, 31.0 mmol) dropwise. After 15 minutes the reaction was complete by HPLC. The contents of the flask were transferred to a separatory funnel, washed twice with water and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl methanesulfonate (6.8 g; 98% yield) as a dark yellow oil that was used as is for the following step. HPLC: 6.18 min (Method D). LCMS: ESI+ m/z of 662 (M+H)
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]3=[O:24])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CN2CCCC2)cc1

Procedure:
1-[2-(4-Pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one is prepared as example 2.1b from 45 mg (mg (0.13 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one (example 2.1a) and 22 μL (0.26 mmol) pyrrolidine. The product is purified via reverse HPLC chromatography (Waters X-Bridge; water (0.15% NH4OH)/acetonitrile 95:5 to 10:90 and then Stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).