Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[C:18]=1[CH2:27][CH2:28][CH3:29]>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14]2[CH:13]=[C:12]([NH:11][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[CH:32]=[CH:31][CH:30]=2)=[C:18]([CH2:27][CH2:28][CH3:29])[C:19]=1[OH:26])(=[O:25])[CH3:24]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: O=C(O)c1cccnc1Cl
Product: CCCc1c(OCc2cccc(Nc3ncccc3C(=O)O)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.1 %

Procedure:
Heat a mixture of 2-chloro-nicotinic acid (132 mg, 0.835 mmol) and 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (250 mg, 0.835 mmol) to 130° C. After 18 hours, cool to ambient temperature and purify via flash chromatography (ethyl acetate:hexanes) to give a residue which was further purified by reverse phase chromatography (methanol:acetic acid:water) to yield the title product as a yellow solid (32 mg, 9%): 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.51 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 5.27 (s, 2H), 6.73 (d, 1H), 6.87 (dd, 1H), 7.06 (d, 1H), 7.34 (t, 1H), 7.67 (d, 1H), 7.81 (d, 1H), 7.88 (s, 1H), 8.26 (dd, 1H), 8.36 (dd, 1H), 10.66 (bs, 1H), 12.85 (s, 1H), 13.63 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(C)cc1

Procedure:
A suspension of 300 g of p-methylcinnamic acid (J. Chem. Soc., Chem. Comm., 471, 1976) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled and filtered to give as a white solid, p-methylcinnamic acid methyl ester, mp 55°-56° C. NMR (DMSOd6) δ=7.36 (d, J=16 Hz, 1H); 7.36 (dd, J1 =30 Hz, J2 =7 Hz, 4H); 6.48 (d, J=16 Hz, 1H); 3.70 (s, 3H); 2.32 (s, 3H). IR (cm-1) 3061, 3028, 2949, 1713, 1634, 1607, 1570, 1516, 1438.
Reaction SMILES: [Cl-].[CH2:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=[O:23])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21](=[O:27])[C:22]([NH:9][CH2:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[O:10])=[O:23])[CH3:19]
Reactant: CCCCOC(=O)C[NH3+]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)CNC(=O)C(=O)OCC
Temperature: 50 °C
Yield: 151.7 %

Procedure:
2-Butoxy-2-oxoethanaminium chloride (573.5 g, 3.42 mol) was suspended in 7 L of ethanol and triethylamine (415 g, 4.1 mol) was added. Diethyloxalate (1.0 Kg, 6.8 mol) was added and the reaction warmed to 50° C. for 3 hours. The reaction was cooled, the volatiles were removed under vacuum and the residue was dissolved in methylene chloride and washed with two 4 L portions of water and dried over MgSO4. The next day the reaction was filtered, evaporated to give ˜1.2 Kg of an oil that was chromatographed on silica eluting with Heptane/EtOAc to give product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CCOCC4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), morpholine (0.024 mL, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.409 mmol) in dichloroethane (1.4 mL) was shaken at ambient temperature for 16 h. Additional portions of morpholine (0.012 mL, 0.14 mmol), sodium triacetoxyborohydride (0.043 g, 0.20 mmol), and acetic acid (0.016 mL) were added and the reaction mixture was stirred at ambient temperature for 24 h. 1 N NaOH (1 mL) was added and the reaction mixture was filtered to afford a gray solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10-60% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21-23 min was collected, concentrated, and lyopholized to afford N1-(4-{4-amino-1-[4-(morpholinomethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.007 g, 0.011 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.34-8.37 (2H, m), 8.14-8.18 (2H, m), 7.97-8.02 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.45-7.51 (2H, m), 7.44 (1H, s), 7.38-7.43 (1H, m), 3.41-3.59 (8H, m), and 3.36 (2H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.72 min. MS: MH+ 622.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([N:42]([C:50]3[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=3)[C:43]([C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)=[O:44])[CH2:38][CH2:37]2)([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][CH:39]([N:42]([C:50]3[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=3)[C:43]([C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)=[O:44])[CH2:40][CH2:41]2)([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CCN(Cc4ccccc4)CC3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCO)CCN(Cc4ccccc4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.6 %

Procedure:
To a solution of N-[1-[2-[1-benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 87) (0.73 g) in tetrahydrofuran (3 mL) was added 1M tetra n-butylammonium fluoride/tetrahydrofuran (1.9 mL). The reaction solution was stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, chloroform-methanol (98:2) ] to give the title compound (0.32 g.)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+:33].C(OCC)(=O)C.Cl>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:9][C:3]=1[C:4]([O-:6])=[O:5].[K+:33]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)[O-])c2)cc1
Yield: 54.4 %

Procedure:
Ethyl 2-hydroxy-5-[[4-[(3-methyl-2-pyridinylamino)sulfonyl]phenyl]ethynyl]benzoate (15.5g, 35 mmol) was refluxed in potassium hydroxide (10 g, 0.15 mol) in water (100 ml) for 1 h. After cooling to ca 70° C., ethyl acetate (50 ml) was added and hydrochloric acid was added to reach pH 7-8. Cooling with stirring and then filtration gave directly 8.5 g of the product (51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>O1CCCC1>[CH2:9]([O:8][C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[N:7]=1)[CH3:10]
Reactant: c1cn[nH]c1
Reactant: CCOc1cc(C)nc(Cl)n1
Solvent: C1CCOC1
Product: CCOc1cc(C)nc(-n2cccn2)n1
Yield: 53.9 %

Procedure:
In anhydrous tetrahydrofuran, 173 mg of 2-chloro-4-ethoxy-6-methylpyrimidine was substituted with 68 mg of pyrazole. The reaction mixture was treated according to the procedure of Example 5 to yield 110 mg of 4-ethoxy-6-methyl-2-(1-pyrazolyl)pyrimidine, an oily compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[C:11]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[C].[Pd]>[CH3:36][N:35]([CH3:37])[C:34]([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1[C:19]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])=[O:38]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc(O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 5 h
Yield: 105.9 %

Procedure:
4′-Trifluoromethylbiphenyl-2-carboxylic acid (4-benzyloxy-2-dimethylcarbamoylphenyl)amide (1.2 g) was dissolved in MeOH (25 mL)-THF (25 mL), and thereto was added 7.5% palladium carbon (250 mg). The mixture was stirred for 5 hours under hydrogen atmosphere. The reaction solution was filtered through a Celite and the filtrate was concentrated to give 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-hydroxyphenyl)amide (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14]OC(OC)N(C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][CH:14]=[CH:12]2
Reactant: COC(OC)N(C)C
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2[nH]ccc2c1C
Reaction time: 0.67 h

Procedure:
A solution of 1-methoxy-2,3-dimethyl-4-nitro-benzene (5.0 g), N,N-dimethylformamide dimethylacetal (7.4 mL) and triethylamine (0.10 mL) in 25 mL of N,N-dimethylformamide was heated to reflux for 3 days under nitrogen. The volatiles were removed in vacuo and the resulting residue was dissolved in 40 mL of a 1:1 mixture of methanol and tetrahydrofuran. Raney nickel (50% slurry in water, 1 mL) was added to the solution, then hydrazine hydrate (2.7 mL) was added dropwise and the mixture was stirred for 40 min under nitrogen. The reaction mixture was filtered through a bed of celite and the filtrate was reduced in vacuo. The product was purified by column chromatography (30% ethyl acetate in hexanes) to yield 1.5 g of pure 5-methoxy-4-methyl-indole.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[C:38]([F:41])([F:40])[F:39].Cl>C(OCC)(=O)C.C(Cl)Cl>[OH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[C:38]([F:41])([F:39])[F:40]
Reactant: OCc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(COc2cccc(-c3c(CO)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-Bromomethylphenylacetic acid (1.86 g, 8.13 mmol) is taken into CH2Cl2 (80 mL) and to this is added Cs2CO3 (9.63 g, 29.56 mmol) and the mixture is stirred for 1 hour. Next, 3-[3-(hydroxymethyl)-8-(trifluoromethyl)quinolin-4-yl]phenol (2.36 g, 7.39 mmol) is added and the reaction is stirred overnight. The reaction is not complete, therefore an additional 3 g of 4-bromomethylphenylacetic acid and 2 g of Cs2CO3 is added and stirring is continued for another overnight period. The reaction is neutralized with HCl and then the solvent is removed. The resulting material is taken up into THF/MeOH/2N NaOH and heated at 70° C. for 45 minutes. The reaction is neutralized with HCl then the organics are removed and the aqueous layer is extracted with ethyl acetate. The combined organics is washed with water and brine and finally dried over Na2SO4. The resulting material is purified via column chromatography using 50% ethyl acetate in hexanes as the eluent to yield a white solid, which still contained an impurity. This material is dissolved into ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer is concentrated to yield the desired product. HRMS: calcd for C26H20F3NO4+H, 468.14227; found (ESI, [M+H]+), 468.1428.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:6].C[N+](C)=[C:9]1[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][O:10]1>>[Br-:6].[C:14]1([C:13]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: C1CCNC1
Agent: [Br-]
Product: c1ccc(C2(c3ccccc3)CCOC2=[N+]2CCCC2)cc1

Procedure:
Compound (G) 1-(3,3-diphenyl-dihydrofuran-2-ylidene)-pyrrolidinium bromide was prepared with pyrrolidine following the same procedure as the synthesis of compound (F) dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C.O>ClCCl>[N:23]1[CH:24]=[CH:25][C:20]([CH:19]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(OCc2ccc(C=O)cc2)cc1
Reactant: Cc1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#Cc1ccc(OCc2ccc(C=Cc3ccncc3)cc2)cc1
Yield: 48.8 %

Procedure:
A solution of 9.8 g (40 mmol) 4-(4-formylphenylmethoxy)-benzonitrile, 4 ml (40 mmol) 4-methylpyridine and 4 ml acetic acid anhydride is heated to 120° C. for 18 h. One mixes with water, extracts with dichloromethane, dries the extract, evaporates and triturates with ether. One isolates 6.1 g of title compound (49% of theory) of the m.p. 149°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:16][CH2:15][C:13]1[N:14]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cccc(NC(=O)OC(C)(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 40.5 %

Procedure:
To a stirred solution of ethyl 6-(tert-butoxycarbonylamino)picolinate (92; 11.0 g, 33 mmol) in THF (120 mL) under nitrogen was added LiAlH4 (3.80 g, 100 mmol) in THF (60 mL) over a period of 30 min at 0° C. The reaction mixture was stirred at 0° C. for 6 h and carefully quenched by the addition of water (2.0 mL) and 10% NaOH solution (4.0 mL) at 0° C. The reaction mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue purified by chromatography (1:1 petroleum ether:ethyl acetate) to afford tert-butyl 6-(hydroxymethyl)pyridin-2-ylcarbamate 93 (3.0 g, 41%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[Na].C1([O-])C2C(=CC=CC=2)C=CC=1>CN(C=O)C.C(O)(=O)C>[CH:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:10]2)=[O:13]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=Cc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=Cc1ccc2cc(OCCCCCCCC(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
The intermediate aldehyde for this compound was prepared by a slightly modified procedure: 6-Hydroxynaphthalene-2-carbaldehyde (1.0 g, 5.8 mmol) was dissolved in DMF (10 mL) and sodium hydride 60% (278 mg) was added and the mixture stirred at RT for 15 min. 8-Bromooctanoic acid (0.37 g, 1.7 mmol) was converted to the sodium salt by addition of sodium hydride 60% and added to an aliquot (2.5 mL) of the above naphtholate solution and the resulting mixture was stirred at RT for 16 hours. Aqueous acetic acid (10%) was added and the mixture was extracted 3 times with diethyl ether. The combined organic phases were dried with MgSO4 and evaporated to dryness affording 300 mg of 8-(6-formylnaphthalen-2-yloxy)octanoic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7][C:8]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 0.865 g 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid methyl ester in 9.0 ml tetrahydrofurane was added 3.2 ml of a 1M of lithium hydroxide in water was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was acidified with 1 M hydrochloric acid. The solid was collected by filtration washed with water and dried under high vacuum to yield 0.805 g of the title compound as white solid, MS (EI): 331.1 (M−H).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:24])[C@H:7]([CH3:23])[N:8]([C:16](=[O:22])[CH2:17][O:18]C(=O)C)[C:9]1[C:13]([CH3:14])=[CH:12][S:11][C:10]=1[CH3:15].O.Cl>CO>[CH3:4][O:5][C:6](=[O:24])[C@H:7]([CH3:23])[N:8]([C:16](=[O:22])[CH2:17][OH:18])[C:9]1[C:13]([CH3:14])=[CH:12][S:11][C:10]=1[CH3:15]
Reactant: COC(=O)[C@H](C)N(C(=O)COC(C)=O)c1c(C)csc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](C)N(C(=O)CO)c1c(C)csc1C

Procedure:
A solution of 5.4 g (0.1 mol) sodium methanolate in 50 ml dry methanol is slowly added to a mixture of 62.6 g (0.2 mol) N-(acetoxyacetyl)-N-(2,4-dimethylthien-3-yl)-alanine methylester (=Ex. 3.5) in 750 ml dry methanol with stirring. The mixture is stirred for two hours at room temperature, then freed of solvent in vacuo. The residue is poured into water and the pH adjusted to pH 2 with 2 N aqueous HCl. The product is extracted with CHCl3, the organic phase washed with water, dried over Na2SO4, and evaporated in vacuo to yield the title compound, m.p. 69°-70°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][N:28]([C:33](=[O:35])[CH3:34])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCc4cccc(F)c4)n2)CNCC3)cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(CCc3cccc(F)c3)c2C1
Yield: 12 %

Procedure:
1-(4-(3-Fluorophenethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (15.8 mg, 12%) was synthesised from 4-(3-fluorophenethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 51a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 471.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=4)[CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[S:49])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=3)[CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:15][C:8]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 125.6 %

Procedure:
To a solution of 74 (235 mg, 0.5 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (159 mg, 0.9 mmol) was added and the reaction was allowed to stir for 30 min. The solvent was removed under reduced pressure and the resulting product was purified by chromatography on silica gel using EtOAc/hexane (1:1) as eluting system to give the desired product (440 mg, 90%) as a white solid. 1H NMR (DMSO) δ (ppm): 8.52 (d, J=5.3 Hz, 1H), 8.01 ( t, J=6.5 Hz, 2H), 7.79 (d, J=7.4 Hz, 1H), 7.70 (s, 1H), 7.53-7.52 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.34 (d, J=4.5 Hz, 4H), 7.30-7.24 (m, 2H), 6.67 (d, J=5.3 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.42 (s, 2H), 3.22 (s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.45-1.33 (m, 9H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[Cl-].C[NH+](C)C.CCCC(C)C>ClCCl.C(OCC)(=O)C>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:12][CH2:13][CH2:14][NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: C[NH+](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A solution of p-toluenesulfonyl chloride (28.40 g, 148 mmol) in dichloromethane (100 mL) was added dropwise over 30 minutes at 0° C. to a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (20 g, 120 mmol), triethylamine (18.80 g, 186 mmol) and trimethylammonium chloride (1.18 g, 12.4 mmol) in dichloromethane (120 mL). The mixture was stirred at 0° C. for 1 hour then filtered, washing with dichloromethane (100 mL). The filtrate was washed with 10% citric acid (3×100 mL) and brine (100 mL). The organic layer was dried with magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was dissolved in ethyl acetate (40 mL) and then iso-hexane (160 mL) was added slowly. The resultant slurry was stirred at room temperature for 17 hours and then filtered. The collected solid was washed with iso-hexane (240 mL) to yield the title compound as a colourless powder (25 g, 64%).