Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH2:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[NH2:14][C:8]1[C:7]([O:15][CH2:16][CH3:17])=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][C:9]=1[O:11][CH2:12][CH3:13]
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOc1cc(CO)cc(OCC)c1N
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (2.8 g, 11.05 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in dichloromethane (50 mL) at 0° C. under Ar was slowly added diisobutylaluminium hydride (27.6 mL, 27.64 mmol, 2.5 equiv; 1.0 M solution in dichloromethane) over a time period of 15 min and the cooling bath removed on completion of addition. After stirring for 18 h, the excess hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (10 mL). The solidified mixture was extracted with dichloromethane (5×200 mL) and THF (2×150 mL), the combined organic phases washed with water (3×100 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) providing 1.10 g (47%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.42 (t, J=7.0 Hz, 3H), 3.82 (br s, 2H), 4.05 (q, J=7.0 Hz, 2H), 4.54 (s, 2H), 6.50 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 15.03, 64.21, 66.00, 104.51, 125.44, 129.89, 146.71. MS (ISP): 211.9 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]1)#[CH:9].[CH2:16]([C:18]([C:29]1[CH:34]=[CH:33][C:32](OS(C(F)(F)F)(=O)=O)=[C:31]([CH3:43])[CH:30]=1)([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)[CH2:19][CH3:20])[CH3:17].C(OCC)(=O)C>C(#N)C.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>[CH2:16]([C:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)([C:29]1[CH:34]=[CH:33][C:32]([C:9]#[C:8][C:10]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:31]([CH3:43])[CH:30]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC1(O)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Triethylamine (5.2 mL, 37.3 mmol), 1-ethynylcyclopentanol (2 g, 18.2 mmol), cuprous iodide (0.24 g, 1.26 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.44 g, 1.25 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 5.2 g, 12.5 mmol) in acetonitrile (52 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred at 110° C. for four hours. Ethyl acetate was added to the residue. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (3 g, 64%).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][C:8]=1[C:9](O)=[O:10].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[ClH:1].[CH3:5][O:4][N:3]([CH3:2])[C:9](=[O:10])[C:8]1[CH:12]=[C:13]([Br:16])[CH:14]=[N:15][C:7]=1[NH2:6]
Reactant: CNOC
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
In a nitrogen flushed flask 3.00 g (30.76 mmol) of N,O-dimetylhydroxylamine hydrochloride and 3.53 g (16.27 mmol) of 2-amino-5-bromonicotinic acid are dissolved in a mixture of 350 ml of dichloromethane, and 30 ml of N-methylmorpholine. 12.70 g (24.40 mmol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) is added and the reaction mixture stirred at room temperature for 5 hours. The mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water and then twice with 100 ml of a 10% aqueous citric acid solution and dried over sodium sulfate. The solvent is evaporated and the resulting oil is dissolved in 300 ml of ether. The precipitate formed is filtered off and discarded. The clear filtrate is concentrated to about half its volume and diluted with 30-60 ml of dichloromethane. The resulting solution is stirred vigorously and a 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting precipitate is complete. The precipitate is filtered off, washed with ether and dried by suction to afford 3.15 g (12.04 mmol, 74% yield) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride as an off-white to beige-brown powder. 1H-NMR (d6-DMSO) δ: 8.24 [1H] d, 7.97 [1H] d, 3.56 [3H] s, 3.26 [3H] s. MS: m/z 260 [MH+]
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[C:7]=1[CH3:16])=[O:5].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>CN(C=O)C>[CH3:3][C:4]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:21][C@H:22]3[O:24][CH2:23]3)[C:8]=2[C:7]=1[CH3:16])=[O:5]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CC(=O)c1oc2cccc(O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1oc2cccc(OC[C@@H]3CO3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a suspension (60 ml) of sodium hydride (1.4 g) in DMF was added dropwise a solution (30 ml) of 4-hydroxy-3-methylbenzo(b)furan-2-yl methyl ketone (6.1 g) in DMF under ice-cooling and the mixture was stirred at room temperature for 30 min. To this reaction mixture was added dropwise under ice-cooling a solution (30 ml) of (S)-glycidyl nosylate (9.1 g) in DMF, and the mixture was stirred for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.1 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9](Br)[CH:10]=1)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([C:20]2[CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:19]=2[Cl:18])[CH:10]=1)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
5-Bromo-6-cyclopentyloxy-3-pyridinecarboxylic acid methyl ester (0.33 g, 1.1 mmol) was dissolved in DMF (3.5 mL). To this solution was added [2-chloro-5-(trifluoromethyl)phenyl]-boronic acid (370 mg, 1.6 mmol), palladium(II)acetate (7 mg), triphenylphosphine (18 mg) and triethylamine (0.46 mL). The whole mixture was heated with stirring at 100° C. for 20 h, cooled to room temperature and partitioned between dichloromethane and a mixture of water and concentrated ammonium hydroxide solution (water/ammonia 4:1 v/v). Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 6:1) to yield 0.27 g of the title compound as a light yellow oil, MS (ISP) 400.4 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:12](O)=[O:13])[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:27]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:35][C:34]=1[C@H:45]1[CH2:49][CH2:48][CH2:47][NH:46]1)(=[O:32])=[O:31])([CH3:29])[CH3:28]>>[CH3:43][N:41]([CH3:42])[C:40](=[O:44])[NH:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([CH:27]([CH3:28])[CH3:29])(=[O:32])=[O:31])=[C:34]([C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:12](=[O:13])[C@H:11]([NH:10][C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:25])[C:1]([NH2:2])=[O:3])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[CH:35]=1
Reactant: CCOc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1[C@H]1CCCN1
Agent: Cl
Product: CCOc1cc([C@@H](Nc2cc(C(N)=O)ccc2F)C(=O)N2CCC[C@@H]2c2cc(NC(=O)N(C)C)ccc2S(=O)(=O)C(C)C)ccc1F

Procedure:
Example 33 was prepared according to the general coupling condition using 29A and 31A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.19 (d, J=6.59 Hz, 3 H) 1.31 (t, J=7.03 Hz, 3H) 1.44 (d, J=6.59 Hz, 3H) 1.68-1.81 (m, 1H) 1.99-2.09 (m, 1H) 2.08-2.19 (m, 1H) 2.40-2.57 (m, 1H) 3.00 (s, 6H) 3.69-3.78 (m, 1H) 3.79-3.89 (m, 1H) 3.90-4.02 (m, 2H) 4.11-4.20 (m, 1H) 5.44 (s, 1H) 5.65 (dd, J=8.35, 5.27 Hz, 1H) 6.80 (d, J=2.20 Hz, 1H) 6.96-7.05 (m, 4H) 7.10-7.19 (m, 1 H) 7.30 (d, J=8.79 Hz, 2H) 7.71 (d, J=8.35 Hz, 1H), LCMS: 672 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Cl)[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1>[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CS
Reactant: O=C(CCCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
344 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and in an atmosphere of nitrogen, to a solution of 0.35 ml of methyl thioglycolate in 90 ml of tetrahydrofuran, and the resulting mixute was stirred at room temperature for 30 minutes. At the end of this time, it was cooled with ice, and a solution of 2.94 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-chloropentanamide [prepared as described in step (a) above] in 30 ml of tetrahydrofuran was added dropwise to the mixture. The reaction mixture was then stirred at room temperature for 2 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 2.84 g (yield 89%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:25])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br.C(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([O:25][CH2:34][CH2:33][O:32][CH3:31])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:13]2)=[CH:6][C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28]
Reactant: COCCBr
Reactant: Cn1c(N2CCN(CC(O)COc3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOC(COc1ccc(Cl)cc1)CN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 1,3-dimethyl-6-[4-(3-[4-chlorophenoxy]-2-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione was dissolved in 30 ml of dimethylformamide, and 0.25 g of sodium hydride (60% and oily) was further added thereto. The solution was stirred at room temperature for 30 minutes, and 0.85 ml of methoxyethyl bromide was then added thereto. After stirring for 3 days, 100 ml of chloroform was added to the reaction solution This solution was washed with water and then dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified through a silica gel column chromatograph (chloroform/methanol=30/1 in volume ratio), thereby obtaining 2.0 g of 1,3-dimethyl-6-[4-(3-[4-chlorophenoxy]-2-(2-methoxyethoxy)propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH2:39]>>[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH:39][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:33])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1)=[O:31]
Reactant: COC(=O)CN
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(-c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1

Procedure:
In analogy to example 89, step 2, from 4′-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (example 95, step 1) and glycine methyl ester hydrochloride was prepared the title compound as light yellow foam, MS (ESI+): m/z=507.2282 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[CH3:31][N:32]1[CH2:35][C:34]2([CH2:38][NH:37][CH2:36]2)[CH2:33]1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:37]2[CH2:38][C:34]3([CH2:35][N:32]([CH3:31])[CH2:33]3)[CH2:36]2)[N:8]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: CN1CC2(CNC2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4(CN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 26.2 %

Procedure:
In THF (15 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (120 mg, 0.27 mmol) and 2-methyl-2,6-diazaspiro[3.3]heptane (45 mg, 0.40 mmol). The solution was cooled in an ice bath, and triethylamine (82 mg, 0.81 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol/triethylamine=10/1/0.008) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid (35 mg, 26% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([Sn:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1OC(=O)N(C2C=CC(I)=C([F:48])C=2)C1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([Sn:22]([CH3:23])([CH3:24])[CH3:25])=[C:20]([F:48])[CH:21]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1

Procedure:
Using essentially the same procedure as described for (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-2-one, but starting from (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (1.97 g, 4.37 mM) gave the title compound as a white solid after chromatography using hexanes then 20% ethyl acetate/hexanes (1.75 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)#[N:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccc(C#N)cc3)c3ccccc3nc21
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-cyanobenzylamine (1.2 g, 9 mmol) was heated on a steam bath for 3 hours, then was allowed to sit at room temperature overnight. The reaction mixture was poured into water and an oil separated. The oil was extracted with hot 10% ethanol/ethyl acetate, washed with water, and the organic layer was dried and evaporated. The residue was crystallized from ether/ethyl acetate and then was purified by recrystallization from ethyl acetate/hexane, followed by column chromatography on silca gel eluting with ethyl acetate and finally crystallization of the residue thus obtained from ethyl acetate/hexane to afford 280 mg of 1-ethyl-N-(4-cyanophenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as yellow crystals, m.p. 233-234° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]2[C:14](=[O:29])[C:15]([CH3:28])([CH2:18][C:19](OC3C=CC=CC=3)=[O:20])[C:16](=[O:17])[N:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:30][OH:31].Cl.NO.[OH-].[K+]>COCCOC.CO>[OH:31][NH:30][C:19]([CH2:18][C:15]1([CH3:28])[C:14](=[O:29])[N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]2[C:16]1=[O:17])=[O:20]
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)C(C)(CC(=O)Oc3ccccc3)C(=O)N12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)C1CCCN2C(=O)C(C)(CC(=O)NO)C(=O)N12
Reaction time: 18 h

Procedure:
2.2 g of phenyl 5-tert.butoxycarbonyl-hexahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-2-acetate in 12 ml of 1,2-dimethoxyethane were treated with 9 ml of methanolic hydroxylamine (prepared by dissolving 1.38 g of hydroxylamine hydrochloride in methanol, adding 1.12 g of potassium hydroxide pellets in methanol to a total volume of 14 ml and filtering the solution before use). After 18 hours, the solvent was removed, 300 ml of ethyl acetate were added and the mixture was washed with dilute sodium chloride solution followed by saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated, there being thus obtained an oil which crystallized from ethyl acetate to give 0.98 g of tert.butyl hexahydro-2-[(N-hydroxycarbamoyl)methyl]-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 157°-165° C. (decomposition).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH2:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[N:15]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:60][O:61][C:62](=[O:67])[C@H:63]([OH:66])[CH2:64][NH2:65].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:60][O:61][C:62](=[O:67])[C@H:63]([OH:66])[CH2:64][NH:65][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([CH2:27][N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=3)[N:15]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H](O)CN
Reactant: O=C(O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-({Indan-5-yl-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoic acid (0.44 g, 0.86 mmol) was dissolved in DMF (10 mL) and 1-hydroxybenzotriazole (0.18 g, 1.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g, 1.29 mmol) were added and the resulting mixture was stirred at room temperature for 1.5 hours. 3-Amino-2(R)-hydroxypropionic acid methyl ester hydrochloride, (R-isoserine methyl ester hydrochloride), prepared as described in WO 02/00612, (0.16 g, 1.03 mmol) and DIPEA (225 μL, 1.29 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added and the mixture was washed with water (2×80 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue (0.35 g) was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:1). This afforded 0.10 g (19%) of 2(R)-Hydroxy-3-[4-({indan-5-yl-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH2:14].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 93.7 %

Procedure:
A solution of 2,4-dichloro-quinazoline obtained in step A of example 1 (125 g, 628 mmol) in THF (1 L) was cooled to 4° C. and 40% aqueous MeNH2 (136 mL, 1.57 mol) was added. The mixture was stirred at ambient temperature for 80 min. The solution was alkalized with saturated aqueous NaHCO3 (pH=9) and concentrated. The precipitate was collected by filtration, washed with H2O and hexane, and dried at 80° C. to give (2-chloro-quinazolin-4-yl)-methyl-amine (114 g, 94%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>ClC(Cl)Cl>[ClH:29].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(c1ccc(F)cc1)N(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1

Procedure:
N-Benzyl-4-(4-fluoroanilino)piperidine (2.8 g), dissolved in trichloromethane (30 cc), is stirred for 18 hours with 4-fluorobenzoic acid chloride (2 cc) and in the presence of triethylamine (5 cc). The reaction mixture is then washed twice with sodium hydroxide solution (3N) (30 cc) thereafter with water (30 cc). The organic phase is then dried over magnesium sulphate and thereafter concentrated under reduced pressure (5.2 kPa). By the addition of a 3.4N solution (5 cc) of hydrochloric acid in isopropanol and recrystallization in acetone/ethanol mixture (50:50 by volume) (100 cc), N-(1-benzyl-4-piperidyl)-N-(4-fluorophenyl)-4-fluorobenzamide hydrochloride (3.2 g) is obtained in the form of a white powder, m.p. 210° C.