Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7]>[Cl-].[Na+]>[CH2:6]([O:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=1)[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 70 °C

Procedure:
To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].I[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:16][CH2:17][CH3:18])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1ccc(C(C)=O)cc1C(=O)OC
Reaction time: 24 h
Yield: 56.3 %

Procedure:
A stirred mixture of methyl 5-acetyl-2-hydroxy-benzoate (10 g, 0.0515 mol), 1-iodopropane (10.5 g, 0.0618 mol), anhydrous potassium carbonate (14.2 g, 0.103 mol) and 2-butanone (200 ml) was heated under reflux for 18 hours. A further quantity of 1-iodopropane (10.5 g, 0.0618 mol) was then added and heating under reflux continued for a further 24 hours. The solvent was removed by evaporation under vacuum and the residue partitioned between water (200 ml) and ethyl acetate (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml), then the organic solutions combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (120 g) using a methanol in dichloromethane elution gradient (0-1%), then crystallization of the product from ethyl acetate-hexane gave the title compound as white crystals (6.85 g, 56%), m.p. 49° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[C:4]([C:12]([F:15])([F:14])[F:13])=[N:3]1.C1(C)C=CC=CC=1.[OH-].[Na+].Cl>O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[C:4]([C:12]([F:13])([F:14])[F:15])=[N:3]1
Reactant: CCOC(=O)c1cn(C)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
50 g of ethyl 1-methyl-3-trifluoromethyl-4-pyrazolecarboxylate were initially charged with 177 g of toluene and 54 g of 25% sodium hydroxide solution and heated to reflux for 15 hours. The cloudy reaction mixture was cooled to 50° C. and admixed with 69 g of water. The aqueous phase was adjusted to pH 1-2 at 30° C. by adding 83 g of 15% hydrochloric acid, and the product precipitated out of solution. The suspension was stirred for a further 30 minutes at room temperature and for 30 minutes at 0° C., and the crude product was then isolated and washed 3 times with 60 g each time of cold (<10° C.) water. After drying at room temperature and under reduced pressure, 43 g of 1-methyl-3-trifluoromethyl-4-pyrazolecarboxylic acid were obtained. This corresponds to a yield of 98% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C([O-])([O-])=O.[Na+].[Na+]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCSc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
2,3-Dichiorothiophenol (4.94 g, 28 mmol) was added to acrylic acid (2.11 g, 29 mmol) and stirred at 50° C. for 3 hours. The reaction mixture was poured into 10% Na2CO3 and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(2,3-dichlorophenylthio)propanoic acid (3.88 g), contaminated with some acrylic acid, as a clear oil which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]#[CH:26]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:26][C:25]#[CH:24])=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(CC)sc12
Temperature: 65 °C

Procedure:
To a stirred solution (pale orange) of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (0.24 g, 1.0 mmol) was dissolved in anhydrous DMF (5 mL) was added cesium carbonate (3.0 eq., 1.0 g, 3.0 mmol) and 1.1 eq. of an 80% solution of propargyl bromide in toluene (0.16 g). The mixture was heated to 65° C. and maintained overnight. The reaction was quenched by slowly adding the reaction mixture to 10 volumes of water (50 mL). The resulting solid was collected by vacuum filtration, rinsed with acetonitrile and air dried, to provide 0.22 g of 2-ethyl-7-[(prop-2-ynyl)oxy]thiazolo[4,5-c]quinolin-4-amine as a pale-peach colored crystalline solid. MS (ACPI) m/z=284 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[C:44]([CH3:45])[C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1cccc(C)c1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl -3-trifluoromethyl-benzenesulfonamide (984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 2.5 mL, 5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of 2-chloro-N-methoxy -3,N-dimethyl-benzamide (852 mg, 4.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (586 mg) in 52% yield. ESMS m/z (relative intensity): 534.9 [(M-32+H)]+ (70), 588.9 (M+Na)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][N:21]([CH3:34])[S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:27]=[CH:26][C:25]([S:22]([N:21]([CH3:34])[CH3:20])(=[O:23])=[O:24])=[CH:30][CH:29]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(S(=O)(=O)N(C)C)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 18.7 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-dimethylaminosulphonylphenylboronic acid (0.046 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes at 250° C. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0079 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:35](C(C2C=NC(Cl)=CC=2)=O)[S:36]([CH3:39])(=[O:38])=[O:37])[C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28](Cl)=[N:27][CH:26]=4)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:49]1([NH2:52])[CH2:51][CH2:50]1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([NH:52][CH:49]5[CH2:51][CH2:50]5)=[N:27][CH:26]=4)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NC1CC1
Reactant: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(Cl)nc4)c3s2)cc(C(C)(C)C)cc1N(C(=O)c1ccc(Cl)nc1)S(C)(=O)=O
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(NC5CC5)nc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 100 °C
Yield: 71 %

Procedure:
To N-(2-{5-tert-butyl-3-[(6-chloro-pyridine-3-carbonyl)-methanesulfonyl-amino]-2-methoxy-phenylcarbamoyl}-benzo[b]thiophen-7-yl)-6-chloro-nicotinamide (see Example 1) (33 mg) in a sealed tube was added 200 μL of cyclopropylamine. The reaction was purged with Ar and heated to 100° C. in the sealed tube 12 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed by NH4Cl solution, water, and brine. The organics were dried over MgSO4, filtered, concentrated down to give a residue which was purified by flash chromatography on silica gel (CH2Cl2-2% MeOH/CH2Cl2) to provide the title compound (21 mg, 71%), m.p. >264° C. dec.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:23](N=P(N(C)C)(N(C)C)N(C)C)(C)([CH3:25])[CH3:24].[Br-]>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:23]=[CH2:24])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), ally) bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20 C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[N:9]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:11][C:3]=12>C(OCC)(=O)C.C(O)(=O)C.[Zn]>[CH:19]([Si:12]([CH:13]([CH3:15])[CH3:14])([CH:16]([CH3:18])[CH3:17])[N:9]1[C:4]2=[N:5][CH:6]=[C:7]([NH2:8])[CH:2]=[C:3]2[CH:11]=[CH:10]1)([CH3:21])[CH3:20]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N)cnc21
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10 g, 32.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Sec-Butyllithium ( 54.8 mL, 1.3M/cyclohexane, 71.4 mmol.) was then added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g, 81.2 mmol.) in THF (100 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and warmed to RT. This mixture was extracted with hexanes (2×200 mL) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 100% hexanes) to afford 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a mixture with starting material (10.2 g). This mixture was directly used in next step. B. 5-Azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 4.6 mmol) was dissolved in ethyl acetate (100 mL) and Pd/C (10%, 100 mg) was added. This suspension was stirred at RT and under 1 atmosphere. of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to afford 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (730 mg, 43.5%, 2 steps). C. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (10.2 g, 31.5 mmol) was diluted in ethyl acetate (200 mL) and acetic acid (100 mL). Zinc dust (50 g, 0.8 mol.) was added in small portions at RT. After stirring the suspension at RT for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×300 mL). The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (6.38 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=[CH:9][C:8]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:20][CH2:19][CH2:18][N:16]1[CH:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([NH2:6])=[C:8]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[CH:9]=2)[CH:14]=[N:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(-c2cnn(CCO)c2)cc1-c1nc2ccccc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (0.072 ml) was added to 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethanol (150 mg, Example 28), triethylamine (0.130 ml) dissolved dichloromethane (5 ml) at 0° C. The resulting suspension was stirred at 0° C. for 2 hours. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 1 to 4% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl methanesulphonate (150 mg) as a solid. NMR Spectrum: (CDCl3) 3.11 (s, 3H), 4.49 (t, 2H), 4.62 (t, 2H), 7.41-7.49 (m, 2H), 7.68 (bs, 2H), 7.78-7.82 (m, 1H), 7.83-7.87 m, 1H), 8.01 (d, 1H), 8.31 (d, 1H), 8.43 (d, 1H), 8.53 (d, 1H); Mass spectrum: M+H+ 400.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23](OC)[C:22](C(OCC)=O)=[C:21]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2].[OH-].[Na+].C(O)(=O)C[C:53](CC(O)=O)([C:55]([OH:57])=[O:56])[OH:54]>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:20]=[C:21]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:45])([F:46])[F:44])[CH:34]=3)[C:22]([O:54][CH2:53][C:55]([OH:57])=[O:56])=[CH:23][N:24]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)nc1OC
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonyl-methoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (128 mg) is dissolved in methanol (3 ml), then thereto is added 1M aqueous sodium hydroxide solution (2 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg). MS (m/z): 658 [M+H]+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: OC1CCCNC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCCC(O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E23 as an off-white solid (0.06 g, 21%). mp 100-102° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B=CH3CN], Gradient elution program: T/% B=0/20, 10/20,25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 41.95 min, 98.43% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:5]=1[C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[C:20]([CH2:28][CH2:29][CH3:30])[CH:19]=2)=[CH:14][CH:13]=1)[CH2:10]Cl)=[O:7].N>O.CN(C)C=O>[F:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:4]([F:3])[C:5]=1[C:6]1[O:7][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:28][CH2:29][CH3:30])[CH:19]=3)=[CH:14][CH:13]=2)[N:8]=1
Reactant: CCCc1cc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)ccc1OC(C)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)ccc1O
Reaction time: 8 h

Procedure:
At −10° C., a solution of 3.7 g (92 mmol) of sodium hydroxide in 10 ml of water is added dropwise with stirring to a solution of 27 g (57 mmol) of 2,6-difluoro-N-[2-chloro-1-(4-(4-acetoxy-3-n-propylphenyl)phenyl)ethyl]-benzamide in 150 ml of dimethylformamide. The mixture is stirred overnight, 43 ml of a 25% strength solution of ammonia are added and the mixture is stirred overnight. The reaction mixture is then poured onto ice-water and extracted repeatedly with ethyl acetate. The combined ethyl acetate extracts are dried over MgSO4 and concentrated under reduced pressure.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11](=[O:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[CH2:6][CH2:7][CH3:8].[CH3:19]O>>[CH2:5]([C:9]1[NH:10][C:11](=[O:18])[CH:12]=[C:13]([C:14]([O:16][CH3:19])=[O:15])[CH:17]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.5 ml (0.17 mol) of thionyl chloride are added dropwise to a suspension of 29.25 g (0.15 mol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 200 ml of methanol, while cooling with ice, and the mixture is stirred overnight at room temperature. It is concentrated to dryness and the residue is chromatographed over 450 g of silica gel (230-400 mesh) using methylene chloride→methylene chloride/methanol 10:1. Colourless crystals of melting point 106° C. crystallise from methylene chloride, ether and petroleum ether.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(O)(=O)C(O)=O.[CH2:30]1[C:33]2([CH2:36][NH:35][CH2:34]2)[CH2:32][O:31]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:35]2[CH2:36][C:33]3([CH2:30][O:31][CH2:32]3)[CH2:34]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1NCC12COC2
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: O=C(O)C(=O)O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CC3(COC3)C2)cn1
Yield: 76 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-oxa-6-aza-spiro[3.3]heptane oxalate instead of methylamine, to the title compound (96 mg, 76%) which was obtained as an off white solid. MS: m/e=392.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1cccnc1

Procedure:
37.4 g (226 mmol) of ethyl pyridin-3-ylacetate in 100 g (679 mmol) of dimethylformamide diethyl acetal are heated at 100° C. overnight. After cooling, the mixture is concentrated and the residue is initially pre-purified by flash chromatography on silica gel (mobile phase: gradient cyclohexane/ethyl acetate 1:1 ethyl acetate/ethanol 9:1). The product obtained in this manner is then subjected to fine purification by distillation under reduced pressure (1 mbar, bath temperature 200° C.).