Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: Cc1ccc(O)cc1C(=O)O
Reactant: CO
Product: COC(=O)c1cc(O)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 107 g 5-hydroxy-2-methylbenzoic acid (compound described in example F1 step 2) in 1000 ml methanol 251.1 g thionylchloride is added dropwise. The mixture is heated to reflux and stirred two hours at RT. After the solvent has been largely evaporated from the mixture under reduced pressure, 100 ml water are added and the reaction mixture is adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is extracted with 200 ml EA three times, the combined organics are dried over MgSO4, and the solvent is removed under reduced pressure yielding methyl 5-hydroxy-2-methylbenzoate, which is used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[NH2:30].CC1C=CC(C)=CC=1>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Solvent: Cc1ccc(C)cc1
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (700 mg, 1.92 mmol), 3-methoxy-5-nitroaniline (645 mg, 3.84 mmol) and p-xylene (7 mL) were combined and heated to 140° C., then stirred for 16 hours at 130° C. The reaction was allowed to cool, placed in a sep. funnel, diluted with DCM, and washed with 2M HCl and brine and concentrated in vacuo. The resulting solid was washed with Et2O to give N-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide (400 mg, 42%). MS (EI) m/z for C21H16N6O7S: 496.94 (MH+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:18][CH3:19])[C:16]#[N:17])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(Cl)Cl.[CH2:25](Br)[Br:26]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:16]([C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1)([CH2:18][CH3:19])[CH2:25][Br:26])#[N:17]
Reactant: BrCBr
Reactant: CCC(C#N)c1ccc(C#Cc2ccccc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C#N)(CBr)c1ccc(C#Cc2ccccc2)cc1

Procedure:
To a solution of 5 g (0.021 mol) 2-[4-(phenylethinyl)phenyl]-butyronitrile in 65 ml CH2Br2 are added, with stirring, 64 g 50% (0.8 mol) NaOH and 5.5 g (0.025 mol) benzyltriethylammoniumchloride. The mixture is stirred for 5 hours at 95°, cooled and 250 ml CH2Cl2 are added. The organic phase is separated off, washed, dried and evaporated in vacuum. The thus obtained title compound is kept for one hour at 70°-80° under high vacuum and crystallises from toluene: ligroine 1:2, m.p. 107°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([CH2:22][P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])=[CH:12][CH:13]([NH:19]C=O)[C:14]([O:16]CC)=[O:15])=[O:5])[CH3:2].C[Si](C)(C)Br.C(O)C>C(Cl)Cl>[NH2:19][CH:13]([CH:12]=[C:11]([CH2:22][P:23]([OH:29])([OH:25])=[O:24])[CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)COCCCC(=CC(N)C(=O)O)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.4 g (5 mmol) of ethyl 7-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate are dissolved in 24 ml of CH2Cl2. Then 2.6 ml (20 mmol) of trimethylbromosilane are added dropwise at room temperature to this solution. The reaction mixture is allowed to stand for 24 hours at room temperature and, after the dropwise addition of 24 ml of ethanol, allowed to stand again for 24 hours. The reaction mixture is concentrated by evaporation and the residue is dissolved in 24 ml of ethanol. A mixture of 24 ml of propylene oxide and 24 ml of ethanol is then added dropwise to this solution. The suspension so obtained is stirred for 1 hour at 0° C. and then filtered with suction. The filter product is dried, giving 2-amino-7-ethoxycarbonylmethoxy-4-phosphonomethyl-hept-3-enoic acid with a melting point of 215°-218° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO>[Cl:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[C:5]([O:23][CH3:24])[C:6]=1[CH:12]1[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15]1
Reactant: COc1c(C(C)=O)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A solution of tert-butyl 3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate (9.6 g, 26 mmol) in methanol (240 mL) at 0° C. was treated with sodium tetrahydroborate (1.9 g, 51 mmol) portionwise over 5 min and stirred at 0° C. for 30 min. The reaction mixture was quenched with acetic acid (7.3 mL, 130 mmol) at 0° C. and treated with saturated sodium bicarbonate solution (˜50 mL). The reaction mixture was concentrated to remove most of the methanol (to ˜60 mL), poured into saturated sodium bicarbonate solution (150 ml), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (9.6 g, quantitative) that was used without further purification. LCMS for C13H16Cl2NO4 ([M-(t-Bu)+]+H)+: m/z=320.0; Found: 320.0.
Reaction SMILES: C[O:2][C:3](=[O:30])/[C:4](=[N:25]/[NH:26][C:27]([NH2:29])=[O:28])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+].ClCCl>CO.O1CCCC1.O>[NH2:29][C:27]([NH:26]/[N:25]=[C:4](\[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)/[C:3]([OH:30])=[O:2])=[O:28]
Reactant: COC(=O)/C(=N/NC(N)=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)N/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 55.7 %

Procedure:
A mixture of (E)-alpha-[(aminocarbonyl)hydrazono]-4-[2-(2-naphthalenyloxy) ethoxy]benzeneacetic acid methyl ester (0.45 g) in warm methanol (3 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (1.25 mL) and after 30 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with a dichloromethane-tetrahydrofuran mixture. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Trituration from dichloromethane provided 0.242 g of pure (E)-alpha-[(aminocarbonyl)hydrazono]- 4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid as a colorless solid, mp 204° C. with decomposition.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([OH:22])=[O:21]>>[CH3:18][CH:17]([S:14]([NH:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)(=[O:16])=[O:15])[CH3:19]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1c1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 108.2 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (245 mg, 0.62 mmol, prepared in example 17) and 4-carboxybenzeneboronic acid (114 mg, 0.69 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with 4% methanol/methylene chloride to afford 260 mg of the title compound which was further purified by semiprep C18 reverse phase HPLC to give 96 mg (40%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[F:12][C:13]([C:16]([CH2:18][CH3:19])=[O:17])([F:15])[F:14].[Cl-].[NH4+]>C1COCC1>[F:12][C:13]([F:15])([F:14])[C:16]([OH:17])([CH2:18][CH3:19])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CCC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(C#C[Si](C)(C)C)C(F)(F)F
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of trimethylsilylacetylene (6.0 g, 61.1 mmol) in THF (80 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (38 mL, 61.1 mmol) was added dropwise. The solution was then stirred 1 hour, before a solution trifluoromethylethylketone (10 g, 79.4 mmol) in 25 mL of THF was added slowly. The reaction was stirred at −78° C. for 4 hours. The reaction was then poured into a saturated ammonium chloride solution and the aqueous layer was extracted (4×) with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 5.83 (s, 1H), 1.80 (q, 2H), 1.14 (t, 3H), 0.18 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13]
Reactant: O=C=Nc1cccnc1
Reactant: CCSc1cc2c(cc1Cl)NCC2
Product: CCSc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 48 %

Procedure:
6-Chloro-5-ethylthioindoline (D64) (0.18 g, 0.85 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.14 g, 48%) as a white crystalline solid m.p.=225°-226° C.
Reaction SMILES: [CH3:1][NH2:2].CO[C:5](=[O:27])[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[N:10]([CH3:20])[C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>ClCCl.CO>[CH3:1][NH:2][C:5](=[O:27])[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[N:10]([CH3:20])[C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN
Reactant: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2cc(Cl)ccc12
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A stream of gaseous methylamine is passed into a 250 ml round-bottomed flask containing a solution of 1.7 g (4.78 mmol) of methyl7-chloro-2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoate in 20 ml of dichloromethane and 80 ml of methanol until saturation and the mixture is left stirring at room temperature for 4 days. The solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 80/20 and then with a 95/5 mixture of dichloromethane and methanol. After recrystallizing from ethyl acetate, 1.36 g (3.83 mmol) of white solid are obtained. Melting point: 161°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:22])=[O:7])=[CH:4][C:3]=1[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Reaction time: 2.5 h

Procedure:
To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid (60 mg, 0.2 mmol) in dry DCM (0.6 mL) was added DMF (1 drop) followed by slow addition of oxalyl chloride (30 μL, 0.34 mmol). The mixture was stirred for 2.5 hrs, then concentrated to yield the corresponding 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl chloride which was dissolved in DCM (1 mL). Cyclopropyl-(2-methoxy-phenyl)-amine (55 mg, 0.34 mmol), followed by diisopropylethylamine (71 μL, 0.4 mmol) were added slowly. The mixture was stirred at room temperature for 12 hrs, concentrated and purified by preparative LCMS to yield 4-chloro-N-cyclopropyl-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide 18-1. MS (M+H)+: 446.9, tR=8.59 min (method 2)
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:37]COC)[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.CO.Cl>[Cl-].[Na+].O.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([OH:37])[CH2:29][NH:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(F)cnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)s2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cnc(C5(O)CNC5)s4)c(F)cnc32)cc1
Temperature: 60 °C

Procedure:
A flask was charged with tert-butyl 3-(5-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)-3-(methoxymethoxy)azetidine-1-carboxylate (Example 54B) (500 mg, 0.849 mmol), methanol (6.5 mL) and aqueous 2 molar HCl solution (2.58 mL, 8.49 mmol). The reaction mixture was heated to 60° C. for 5 hours, then 35° C. overnight. The reaction mixture was cooled to room temperature and diluted with saturated aqueous brine solution and ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate (3×20 mL). The organic layers were combined and concentrated. The remaining solid was triturated with water (pH approximately 10). The solids were collected by vacuum filtration, washed with water, and dried at low temperature in a vacuum oven to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, 1H), 8.40 (s, 1H), 8.10 (d, 1H), 8.01 (d, 2H), 7.44 (d, 2H), 7.14 (d, 1H), 7.06 (s, 1H), 3.96 (d, 2H), 3.71 (d, 2H), 2.35 (s, 3H); MS APCI(+) m/z 445.22 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:10][CH:9]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=1)([CH3:26])[CH3:27]
Reactant: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccc(C(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1

Procedure:
In a similar manner to that described in Reference example 3 (g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (16.2 g), which is the product of Reference example 5(f), triethylamine (12.1 ml) and methanesulfonyl chloride (5.05 ml) and the reaction mixture was treated to afford the desired compound (19.6 g) as a syrup.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.CON(C)[C:13](=[O:24])[C@@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:15].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:15])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1Cl
Temperature: -20 °C
Yield: 65.5 %

Procedure:
To 11.0 g of 2-bromo-3,5-dichloropyridine in 5 ml of tetrahydrofuran, 36.4 ml of a 1.3 M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 15 minutes. Then, to the reaction mixture, 5.0 g of (S)—N-methoxy-N-methyl-2-(tert-butoxycarbonylamino)propionamide in 36 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of saturated aqueous ammonium chloride and 10 ml of water and extracted with ethyl acetate (40 ml×2), the resulting organic layers were combined, washed with water (40 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 10:0 to 3:7) to obtain 4.5 g of the desired product as a pale yellow oil.
Reaction SMILES: Br.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[O:16][CH2:17][CH2:18][N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[O:16]1[CH2:17][CH2:18][N:19]=[C:15]1[N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NCCO2)CC1
Agent: Br
Agent: Cl
Solvent: C1COCCO1
Product: C1COC(N2CCNCC2)=N1

Procedure:
430 mg 4-(4,5-dihydro-oxazol-2-yl)-piperazine-1-carboxylic acid tert-butyl esterhydrobromide was stirred in 5 mL 4 M HCl solution in dioxane for 20 min. The mixture was filtered to give 165 mg of the desired product. Rt: 0.88 min (method B), (M+H)+: 156
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=3[C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH:36]([C:40]([O:42]C)=[O:41])[CH2:35]3)=[O:32])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[C:40]([CH:36]1[CH2:37][CH2:38][CH2:39][CH:34]([NH:33][C:31]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=2[O:20][CH2:19][CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=2)[C:25]([OH:27])=[O:26])=[O:32])[CH2:35]1)([OH:42])=[O:41]
Reactant: COC(=O)c1ccc(OCCCc2ccc(OCCCC3CCCCC3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCCCc2ccc(OCCCC3CCCCC3)cc2)c(C(=O)NC2CCCC(C(=O)O)C2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 90.73 g of methyl 4-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate in 500 ml of THF and 500 ml of methanol is mixed with 300 ml of 2 molar sodium hydroxide solution and heated to 60° C. After one hour, the organic solvents are removed as far as possible in a rotary evaporator. 325 ml of 2 molar hydrochloric acid are added to the residue with stirring. A precipitate separates out during this and is filtered off with suction and washed with water. The product is purified by recrystallization from a mixture of 500 ml of acetone and 1000 ml of water. 77.5 g of product are obtained. m.p.: 160° C.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[K+:33].CCCCCC>C(O)C>[K+:33].[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CCC(=O)O)cnc23)ccc(C(C)=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: CCCc1c(OCc2cccn3c(=O)c(CCC(=O)[O-])cnc23)ccc(C(C)=O)c1O
Yield: 73 %

Procedure:
0.50 g (1.18 mmoles) of 3-[9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3yl]propionic acid was suspended in 20 ml of ethanol, and 3.90 ml (1.18 mmoles) of a 2% ethanolic solution of potassium hydroxide was added thereto. This suspension was stirred until a clear solution was obtained. To the resulting reaction solution was added a small amount of n-hexane. The solid matter which separated out was collected by filtration and then dried to obtain 0.40 g (73% yield) of 3-[9-(4-acetyl-3-hydroxy-2-n-propyl-phenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]propionic acid potassium salt in the form of white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([OH:22])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:22][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate (71.05 g, 195 mmol), imidazole (18.52 g, 272 mmol), tert-butyldimethylsilyl chloride (32.23 g, 214 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.6 mmol) in DMF (270 ml) was left to stir at room temperature under a nitrogen atmosphere for a period of 24 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was separated and washed with 2N hydrochloric acid (2-fold 500 ml), saturated aqueous sodium bicarbonate (2×500 ml) saturated sodium chloride (500 ml), dried (magnesium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (91.0 g).