Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[S:15][CH:14]=[C:13]([C:16]3[S:20][C:19]([NH:21]C(=O)C)=[N:18][C:17]=3[CH3:25])[CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[ClH:26].CCO>>[ClH:26].[NH2:21][C:19]1[S:20][C:16]([C:13]2[CH:12]=[C:11]([S:8]([N:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)(=[O:10])=[O:9])[S:15][CH:14]=2)=[C:17]([CH3:25])[N:18]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCC(O)CC3)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(S(=O)(=O)N2CCC(O)CC2)c1
Temperature: 90 °C

Procedure:
To N-(5-{5-[(4-hydroxypiperidin-1-yl)sulfonyl]-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide (39) (400 mg; 1 mmol; 1 eq) is added hydrochloric acid 1.25 M in EtOH (16 ml; 1.25 M; 19.9 mmol; 20 eq) and the mixture is heated at 90° C. for 8 h30. The reaction mixture is cooled down to RT and a precipitate is formed. It is filtered and washed with cold EtOH, affording the hydrochloride salt of Compound (45) as light yellow powder (328.3 mg; 83%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>CO.ClCCl>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:43](=[O:44])[CH2:42][O:41][CH3:40])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: COCC(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COCC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol, Example 1) was dissolved in methanol (0.5 mL) and dichloromethane (3 mL). Triethylamine (0.013 mL, 0.09 mmol) was added followed by methoxyacetyl chloride (8.55 μL, 0.09 mmol). The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated under reduced pressure. The crude was dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxyethanone (8.4 mg, 16.96%). HPLC, ms detection: (ESI) (M+1) m/z 501;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(Cl)CCl.C(N(CC)CC)C.Cl>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In a 1 L round-bottomed flask, a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (21.0 g, 80 mmol) in anhydrous dichloromethane (250 mL) was stirred at room temperature until completely dissolved. After becoming clear, the reaction mixture was cooled to 0° C. and sequentially treated with N,O-dimethylhydroxylamine hydrochloride (9.74 g, 100 mmol), EDC (19.2 g, 100 mmol), and triethylamine (30.4 g, 41.81 mL, 300 mmol). After the additions were complete, the reaction mixture was stirred at room temperature overnight. 1 N HCl (250 mL) was added and after 5 min of additional stirring, the organic phase was separated, washed with 1 N HCl (100 mL), saturated aqueous NaHCO3 (150 mL), dried over MgSO4, filtered and concentrated. Purification by MPLC (100 g column, 50-100% ethyl acetate in heptane) gave benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (22.23 g, 91%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.42-7.29 (m, 5H), 5.21 (s, 2H), 4.32-4.16 (m, 2H), 3.70 (s, 3H), 3.18 (s, 3H), 2.96-2.78 (m, 3H), 1.80-1.64 (m, 4H). ESI MS found for C16H22N2O4 m/z [307.1 (M+1), 329.2 (M+23)].
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][C:8]([CH3:15])=[CH:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:3]#[CH:4]>C1C=CC=CC=1.[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:12](=[CH:11][CH2:10][CH2:9][C:8]([CH3:15])=[CH:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:16])[CH:3]=[CH:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:13]
Reactant: C#CC(C)(O)CCCC(C)=CCC=C(C)C
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)(O)C#CC=CC(C)(O)CCC=C(C)CCC=C(C)C
Yield: 94 %

Procedure:
In contact with triphenylphosphine rhodium chloride [RhCl (PPh3)3 ] catalyst, 3,7,11-trimethyl-7,10-dodecadien-1-yn-3-ol was refluxed in benzene for 3 hours. The reaction mixture was concentrated and purified by column chromatography (developer system: benzene-chloroform=1:1). Analysis of the product by gel permeation chromatography showed that the starting material had substantially reacted to yield 2,6,10,15,19,23-hexamethyl-2,6,11,18,22-tetracosapentaen-13-yn-10,15-diol (94% selectivity). The resulting acetylenic diol was hydrogenated in n-hexane and in contact with 5% palladium-on-carbon at room temperature and elevated pressure of 80-100 kg/cm2 to yield 2,6,10,15,19,23-hexamethyltetracosa-10,15-diol (bp. 218°-220° C./0.2 mm Hg). This product was subjected to hydrogenolysis in acetic acid in contact with palladium-on-carbon at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 170°-190° C. The resultant compound was analyzed by gas chromatography and nuclear magnetic resonance spectroscopy and the data conformed with a standard sample of squalene.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:8]=[C:9]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:3]1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[NH:20]1[CH2:21][CH2:22][C@@H:18]([O:17][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[N:8]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2cc3ccccc3c(O[C@@H]3CCNC3)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To crude (R)-tert-butyl 3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate was added a minimal amount of NMP and TFA (2 mL). The solution was stirred at RT for 10 minutes and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 15-22% ACN in water (acid mode) to give the title compound (229 mg, 29% over 3 steps).
Reaction SMILES: BrNC(=[O:5])C.[OH:6][C@H:7]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:26]2[CH2:25][C@@H:24]([OH:31])[C@@:23]2([CH3:32])[C:13]3=[CH:14][CH2:15][C@@H:16]2[C:17]2([O:22][CH2:21][CH2:20][O:19]2)[CH3:18])[CH2:8]1.O.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.C(O)(=O)C>[OH:6][C@H:7]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:9]3([O:5][CH:10]3[CH2:11][C@@H:12]3[C@@H:26]2[CH2:25][C@@H:24]([OH:31])[C@@:23]2([CH3:32])[C:13]3=[CH:14][CH2:15][C@@H:16]2[C:17]2([O:19][CH2:20][CH2:21][O:22]2)[CH3:18])[CH2:8]1
Reactant: CC1([C@H]2CC=C3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@@H](O)[C@@]32C)OCCO1
Reactant: CC(=O)NBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC1([C@H]2CC=C3[C@@H]4CC5OC56C[C@@H](O)CC[C@]6(C)[C@H]4C[C@@H](O)[C@@]32C)OCCO1
Reaction time: 0.5 h

Procedure:
N-Bromoacetamide (211 mg, 1.5 mmol) is added to a stirred solution of the 5,14-diene (23) (500 mg, 1.34 mmol) in acetone (100 ml), acetic acid (2.5 ml), and water (5 ml) at 0° C. After 15 min sodium sulphite (5% soln, 50 ml) is added to the reaction mixture. The acetone is evaporated, and the aqueous layer extracted with dichloromethane (3×50 ml). The organic layer is dried (MgSO4), filtered and evaporated. Pyridine (1 ml) is added to the product, and stirred for 0.5 h. Dichloromethane (100 ml) is then added to the reaction mixture, and the dichloromethane is washed with citric acid (5% soln, 3×100 ml), saturated sodium bicarbonate (50 ml), and water (50 ml). The organic layer is dried (MgSO4), filtered and evaporated to give the mixture of 14,15- and 5,6-epoxides (360 mg, 69%) as a white foam. The mixture of epoxides could not be separated by silica gel column chromatography.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:15]=[N-:16]>C(O)C>[N:14]([C:17](=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:4]=1[O:3][CH3:2])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:15]=[N-:16]
Reactant: COc1cccc(C=O)c1OC
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc(OC)c1OC)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Pieces of sodium (3.678 g, 160 mmol) were added to ethanol (200 ml) over a period of 30 minutes. The resulting solution was cooled to −18° C. and a mixture of 2,3-dimethoxybenzaldehyde (4.832 g, 40 mmol) and ethyl azidoacetate (20.64 g, 160 mmol) was then added, over one hour, at a rate which allowed the temperature to be maintained below −15° C. After three hours, the solution was stored at 5° C. for two days in order to give a crystalline product which was collected. and washed with cold hexane in order to give a pure product in the form of a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8](=[O:28])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[S:10][C:5]=2[CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8](=[O:28])[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[S:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)SC(CCCCN1CCN(c3cc(C)ccn3)CC1)C(=O)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(N2CCN(CCCCC3Sc4cc(O)ccc4NC3=O)CC2)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
360 mg of 7-methoxy-2-{4-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-butyl}-2H-1,4-benzothiazine-3(4H)-one (see Example 19) prepared analogously to Example 1 were added to 5 ml of dichloromethane with exclusion of moisture. After cooling to -5° C., a solution of 0.73 g of boron tribromide in 1 ml of methylene chloride was added dropwise with stirring. Stirring was then continued for a further 30 minutes at room temperature. The reaction mixture was worked up by adding it with stirring to a mixture of ice and aqueous sodium hydrogen carbonate solution. 200 ml of chloroform were then added. The resulting organic solution was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained from the remaining residue by fractional column chromatography. The fractions containing the title compound were concentrated and treated with ether. 30 mg of 7-hydroxy-2-{4-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]butyl}-2H-1,4-benzothiazine-3(4H)-one were obtained as white crystals having a melting point of 212° C.
Reaction SMILES: [H-].[Na+].C(S)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16]C)[CH:15]=1)[CH:11]=[O:12].[Cl-].[Na+].C=O>CN(C)C=O.C(O)(=O)C>[OH:16][C:14]1[CH:13]=[C:10]([CH:9]=[C:8]([O:7][CH3:6])[CH:15]=1)[CH:11]=[O:12]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: C=O
Agent: [Cl-]
Agent: [H-]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(O)cc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of 60% sodium hydride (2.77 g, 69.3 mmol) in N,N-dimethylformamide (50 ml) was gradually added at 0° C. ethanethiol (7 ml), and the solution was stirred at 0° C. for 30 minutes, followed by refluxing under heating for 1 hour. The mixture was cooled to room temperature, and thereto was added 3,5-dimethoxybenzaldehyde (3.84 g, 23.1 mmol) in N,N-dimethylformamide (90 ml) and the mixture was refluxed under heating for 1 hour. The mixture was cooled to room temperature, and thereto were added a saturated aqueous sodium chloride solution (700 ml), 26% aqueous formalin solution (70 ml) and acetic acid (130 ml) in the order. The mixture was stirred, extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography. (hexane:ethyl acetate=2:1) to give the subject compound (2.68 g, 17.6%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][OH:14].[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CS(C)=O.C1C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][O:14][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: O=C1c2ccccc2OCN1CCO
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=Cc1ccc(OCCN2COc3ccccc3C2=O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.58 g (3.0 mM) of 2-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-ethanol was dissolved in 5.0 ml of dimethyl sulfoxide. After the addition of 0.18 g (4.5 mM) of sodium hydride (oil) under ice cooling, the mixture was stirred for one hour while heating at 40° C. Then, 0.56 g (4.5 mM) of p-fluorobenzaldehyde in 5.0 ml of benzene was gradually added dropwise under ice cooling. After the addition, the mixture was allowed to stand room temperature while stirring for one hour. After the reaction, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The oil phase was combined and washed once with water, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified with a silica gel column (eluent, hexane:ethyl acetate=5:1) to obtain 0.56 g (yield 62%) of colorless crystals of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[N:10]2)=[CH:5][CH:4]=1.[C:18]1([C@H:28]([NH2:30])[CH3:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.ClCCCl>[C:18]1([C@H:28]([NH:30][CH2:14][C:11]2[CH:12]=[CH:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[N:10]=2)[CH3:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=Cc1ccn(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H](NCc1ccn(-c2ccc(C(F)(F)F)cc2)n1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 65 (0.200 g, 0.833 mmol), (R)-1-(naphthalen-1-yl)ethanamine 39 (0.171 g, 0.999 mmol), sodium triacetoxyborohydride (0.353 g, 1.67 mmol), 4 mL of DCE, and 3 drops of AcOH. This mixture was stirred overnight at room temperature and then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, and concentrated. Purification by column chromatography on silica gel (10% to 50% EtOAc in hexanes) gave ((1R)-1-(1-naphthyl)-N-({1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}methyl)ethanamine 66. Mass spectrum, calculated for C23H20F3N3 395.2; found 396.2 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C.[OH-].[Na+]>>[C:40]([CH2:39][CH2:38][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])([OH:42])=[O:41]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1
Yield: 98.6 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (210 mg, 0.34 mmol) and 1.0 N aqueous sodium hydroxide (3.4 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethoxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (190 mg, 99%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C33H39FO7 (M+Na)+ 589.2572. found 589.2573.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O.CC(=O)OCC>C(Cl)Cl>[NH2:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:8]#[N:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#C[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl((trans-4-cyanocyclohexyl)methyl)carbamate (1.4 g, 5.86 mmol) in CH2Cl2 (20 mL) was added TFA (20 mL) at r.t. The resulting mixture was stirred at room temperature for 1 h. TLC (PE:EA=5:1) showed the reaction was complete. The mixture was concentrated in vacuo to give trans-4-(aminomethyl)cyclohexanecarbonitrile (2.6 g, 319%) as TFA salts.
Reaction SMILES: [CH3:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[N:7]([N:8]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:9])[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccccc2)c(=O)n1N
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1nnc(-c2ccccc2)c(=O)n1N=Cc1ccccc1

Procedure:
10.1 g (0.05 mol) of 3-methyl-4-amino-6-phenyl-1,2,4-triazin-5-one, 10 g (0.09 mol) of benzaldehyde, 0.3g of p-toluenesulphonic acid and 300 ml of benzene were boiled for 8 hours under a water separator. Thereafter the reaction mixture was filtered and the solvent was distilled off in vacuo. The residue solidfied after trituration with petroleum ether.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O1CCOCC1.[C].[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cccc(Nc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A mixture of 3-nitro-2-[(m-tolyl)amino]pyridine (825 mg) and 10% palladium carbon (0.3 g) in ethanol (15 ml) and 1,4-dioxane (15 ml) was stirred under hydrogen (3 atm) at room temperature for 30 minutes. The catalyst was removed and the solvent was evaporated. The solids were collected and washed with isopropyl ether to give 3-amino-2-[(m-tolyl)amino]pyridine (660 mg).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si](CC)(CC)CC)=[N:10][C:5]2=[N:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([CH3:22])[CH2:12][OH:13])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][C:25]=1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC[Si](CC)(CC)OCC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Product: CC(C)(CO)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
3-Bromo-7-(1,1-dimethyl-2-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was coupled to 4-fluoro-3-(pyridin-3-yl)benzeneboronic acid (323 mg, 1.28 mmol) following the procedure in Example 65 and deprotected as described in Example 8 to give 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]-2-methylpropan-1-ol as a white powder: δH (360 MHz, CDCl3) 1.39 (6H, s), 3.54 (1H, t, J 7), 3.89 (1H, d, J 7), 6.99 (1H, d, J 7), 7.35-7.45 (2H, m), 7.51-7.60 (2H, m), 7.83 (1H, s), 7.90-7.94 (1H, m), 8.53 (1H, d, J 7), 8.68 (1H, dd, J 5 and 2), 8.83 (1H, s); m/z (ES+) 363 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Br-].[Na+]>C1(=O)OC(C)CO1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Agent: [Br-]
Agent: [Na+]
Solvent: CC1COC(=O)O1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 10 h
Yield: 94 %

Procedure:
As in Example 1, 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) was silylated and the toluene was distilled off to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (16.21 g) and sodium bromide (2.09 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 10 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 1 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (27.02 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH2:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH3:11]
Reactant: [H][H]
Reactant: CC(=C[Si](C)(C)C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C[Si](C)(C)C)c1ccccc1N
Yield: 74.1 %

Procedure:
The reaction product of step A [7.2 g] was hydrogenated in tetrahydrofurane over palladium on charcoal at atmospheric pressure and room temperature until the uptake of hydrogen ceased. The catalyst was filtered off and, after evaporation of the solvent, the product was chromatographed on silacagel (eluent: 10% ethylacetate in hexane) to yield 2-(2-aminophenyl)-3-(trimethylsilyl)-propane [4.7 g; 88% purity according to NMR]. This product was used in the next step without further purification.