Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:35][CH2:36]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH2:39][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])[CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC1

Procedure:
A mixture of 200 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline and 0.11 ml of ethyl acrylate in 2 ml of ethanol is heated under reflux for one hour. The solvent is evaporated in vacuo and the crude product is purified by column chromatography on silica gel with methylene chloride/methanol (95:5 to 90:10) followed by recrystallization from diethyl ether. Yield: 164 mg (69% of theory), Melting point: 183-185° C. Mass spectrum (ESI−): m/z=609, 611 [M−H]−
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:29][N:30]=1)=[CH:9]2.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][N:30]=1)=[CH:9]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of ethyl (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (960 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred for 50° C. for 1 hr. 1N Hydrochloric acid (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (800 mg, yield 88%) as a yellow amorphous solid. The solid was crystallized from ethyl acetate-hexane, and recrystallized from ethyl acetate-hexane to give pale-yellow powder. melting point 107-109° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([O:15][C@@H:24]1[CH:25]2[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]2)[CH2:23]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a solution of 2-(benzyloxycarbonylamino)-2-phenylacetic acid (I28) (855 mg, 3.00 mmol) in THF (20 ml), were added (R)-quinuclidin-3-ol (457 mg, 3.60 mmol), N,N′-methanediylidenedicyclohexanamine (742 mg, 3.60 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (486 mg, 3.60 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the clear solution was washed twice with Na2CO3 and brine, dried over Na2SO4 and evaporated. The resulting crude is purified by silica gel flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzyloxy-carbonylamino)-2-phenylacetate (925 mg; 78% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([C@@H:27]3[CH2:28][C@H:26]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:30])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenyl-1-cyclopropanecarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-(trans)-2-phenylcyclopropane-1-carboxamide as an off white solid, m.p. 77.0° C. 1H NMR (300 MHz, DMSO-d6) δ7.90 (dd, J=8.1, 1.2 Hz, 1H), 7.81 (dd, J=8.1, 1.2 Hz, 1H), 7.78 (s, 1H), 7.50 (dt, J=8.1, 1.5 Hz, 1H), 7.33-7.15 (m, 4H), 7.05-7.02 (m, 2H), 5.84 (broad s, 1H), 5.51 (s, 2H), 4.52 (t, J=7.2 Hz, 2H), 3.32 (q, J=6.6 Hz, 2H), 2.49-2.43 (m, 1H), 2.07-1.95 (m, 3H), 1.64-1.51 (m, 3H), 1.25-1.18 (m, 1H); IR (KBr) 3304, 3179, 2939, 1640, 1582, 1527, 1479, 1396, 1250, 755, 735, 689 cm−1; MS (EI) m/e 399.2059 (399.2059 calcd for C24H25N5O).
Reaction SMILES: N#N.[C:3]([C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)[O:9][CH:10]=1)(=[O:5])[CH3:4].[CH3:33][Al](C)C.[Cl-].[NH4+].Cl>C(Cl)Cl.CCCCCCC>[OH:5][C:3]([C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)[O:9][CH:10]=1)([CH3:33])[CH3:4]
Reactant: C[Al](C)C
Reactant: CC(=O)c1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(C)O)co3)n2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of N-(2-((4-acetyloxazol-2-yl)methyl)-2H-1,2,3-triazol-4-yl)-2-methyl-5-(m-tolyl)oxazole-4-carboxamide (622 mg, 1.53 mmol) in CH2Cl2 (15 mL) was treated at 0° C. with AlMe3 (2.3 mL of a 2.0M solution in heptane, 4.6 mmol) and the resulting mixture was stirred for 2 h at 0° C. The reaction mixture was carefully poured into a sat. aq. solution of ammonium chloride (10 mL) and diluted with CH2Cl2 (20 mL). 1N HCl (10 mL) was then added. The layers were separated and the org. phase was dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a white solid: TLC: rf (3:7 hept-EA)=0.28. LC-MS-conditions 06: tR=0.85 min, [M+H]+=423.17.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[CH3:3].[N+](=[CH2:24])=[N-]>C(OCC)C>[CH3:3][C:2]([CH3:1])([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([O:18][CH3:24])=[O:17])=[CH:10][CH:9]=1)[CH3:21]
Reactant: CC(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)Cc1ccc(OCC(=O)OC(C)(C)C)cc1

Procedure:
Dissolve (+)-4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid (90% ee) (6.04 g, 20.5 mmol) in ethyl ether (400 mL) and treat with excess diazomethane. Wash with saturated sodium hydrogen carbonate (2×300 mL) and brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give (+)-4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid, methyl ester (5.85 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cccc(F)c1F
Agent: N
Product: Fc1cccc(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.51-7.67 (m, 2H), 8.08-8.14 (m, 1H), 8.18 (ddd, J=10.7, 7.5, 2.0 Hz, 1H), 8.55 (dt, J=8.0, 1.9 Hz, 1H), 8.74 (dd, J=5.2, 1.6 Hz, 1H), 9.29 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 260 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([N:13]2[C:17](=[O:18])[C:16](=[N:19][NH:20][C:21]3[C:22]([OH:36])=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33](O)=[O:34])[CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[C:15]([CH3:37])=[N:14]2)[CH:9]=[CH:10][C:11]=1[CH3:12].CN(C=O)C>C1COCC1.CCCCCCC>[CH3:5][C:6]1[CH:7]=[C:8]([N:13]2[C:17](=[O:18])/[C:16](=[N:19]\[NH:20][C:21]3[C:22]([OH:36])=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([Cl:3])=[O:34])[CH:28]=4)[CH:24]=[CH:25][CH:26]=3)/[C:15]([CH3:37])=[N:14]2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)Cl)c2)c1O
Reaction time: 1 h
Yield: 96 %

Procedure:
Thionyl chloride (5 mL, 68.5 mmol) was added to a solution of pure 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (Eltrombopag form I) (5 g, 11 mmol) in dry THF (75 mL) followed by addition of DMF (0.5 mL) at room temperature in three-necked flask. The reaction mixture was stirred for one hour and additional thionyl chloride (5 mL, 68.5 mmol) and DMF (0.5 mL) were added. The precipitation of acyl chloride started in half an hour and heptane (90 mL) was added. The thick reaction suspension was stirred for further half an hour, filtrated and washed with 2×50 mL of heptane yielding 5 g of (Z)-3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carbonyl chloride (Yield: 96%); (HPLC: 95%), that was immediately used for the next step.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([CH2:50]C(Cl)=O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:50]([C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:5])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCc1cccc2cncn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCc1cccc2cncn12
Reaction time: 2 h

Procedure:
5-(5-Ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine (1091 g) is charged into a 12 liter round bottom flask under a nitrogen atmosphere. Ethyl alcohol (95%, 420 ml) is added while stirring. With continued stirring, 2 N NaOH (2100 ml) is added in portions. After complete addition the mixture is warmed at 70° for 20 minutes, at which time a solution is obtained, and heating is continued for 2 hours. Additional sodium hydroxide (50% solution, 21 ml) is added and heating is continued for 40 more minutes. The reaction mixture is cooled, 12 N HCl (30 ml) is added, and the ethyl alcohol is partially removed by evaporation under reduced pressure. The resulting solution is washed with ethyl ether (1700 ml), decolorized with charcoal, filtered, and acidified with acetic acid (300 ml). The product that crystallizes at 4° overnight is collected, washed first with water, then with ethyl ether (1000 ml), and dried to give 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine, melting at 146°-8°, and identical to the product of Example 2.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[C@@:20]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[O:39][CH3:40])([F:31])[C:19]2=[O:41])=[O:15])=[N:10][N:9]=[N:8]1>CC#N.O>[NH:10]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[C@@:20]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[O:39][CH3:40])([F:31])[C:19]2=[O:41])=[O:15])=[N:7][N:8]=[N:9]1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CCc2nnnn2COCC[Si](C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CCc2nnn[nH]2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Yield: 87 %

Procedure:
(S)-(3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indolin-1-yl)methyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)propanoate (XIII2) (0.30 g, 0.47 mmol) was dissolved in CH3CN (30 mL) and treated with aqueous HF (3 mL, 48% in H2O), and stirred at rt. until the starting material was completely consumed (as judged by HPLC). The mixture was neutralized with aqueous NaHCO3, and the CH3CN removed under reduced pressure. The aqueous layer was extracted with EtOAc, and the organic layer was then dried over MgSO4, filtered and concentrated. The isolated white solid was lyophilized to afford the title compound (0.21 g, 83% yield). 1H NMR (500 MHz, DMSO): δ 2.93 (t, J=7.32, Hz, 2 H), 3.14 (t, J=7.32 Hz, 2 H), 3.50 (s, 3 H), 5.89 (d, J=10.99 Hz, 1 H), 5.91 (d, J=10.99 Hz, 1 H), 7.02 (d, J=8.55 Hz, 1 H), 7.48 (s, 2 H), 7.52 (dd, J=2.44, 8.55 Hz, 2 H), 7.70 (s, 1 H), 7.72 d, J=2.44 Hz, 1 H). LRMS: 514 (M+H). HRMS Calculated 512.8270 (M−H). found 512.8266.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
Prepared as described above in Example 60 starting from 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminoethanol to give the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.92 (s, 6H), 2.12 (s, 3H), 2.95 (br s, 2H), 3.30 (br s, 2H), 3.45 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.92 (m, 2H), 7.17 (m, 5H). LC MS (m/e)=419.4 (MH+). Rt=1.84 min.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]([O:37]CC)=[O:36])=[C:32]=[O:33]>ClCCl>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:32]([NH:31][CH2:34][C:35]([OH:37])=[O:36])=[O:33])=[C:10]([OH:14])[N:9]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CC(=O)N(C2CCOCC2)C(=O)N1C1CCCCC1
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)n(C2CCOCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. 1-Cyclohexyl-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)-pyrimidinetrione (900 mg, 3.06 mmoles) and diisopropylethylamine (1.06 mL, 6.12 mmoles) were stirred together in dry dichloromethane (50 mL) and treated with ethyl isocyanatoacetate (360 uL, 3.21 mmoles). The mixture was stirred for under argon overnight, washed twice with 1 molar hydrochloric acid, dried and evaporated. The residue was dissolved in ethanol (15 mL) and treated with 1 molar sodium hydroxide solution (2.0 mL) and 6 molar sodium hydroxide solution (2.0 mL) and stirred for 4 hours. The mixture was partitioned between ethyl acetate and 1 molar hydrochloric acid, the organic solution washed with 1 molar hydrochloric acid, dried and evaporated to a solid. The solid was triturated with diethyl ether, collected, washed with a small amount of diethyl ether and hexane to afford the title compound (570 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s, 1 H), 10.19 (t, J=5.56 Hz, 1 H), 4.83-4.94 (m, 1 H), 4.63 (t, J=11.49 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.93 (dd, J=11.12, 4.04 Hz, 2 H), 3.30-3.37 (m, 2 H), 2.56 (m, 2 H), 2.21-2.33 (m, 2 H), 1.79 (d, J=12.88 Hz, 2 H), 1.61 (s, 3 H), 1.52 (d, J=10.61 Hz, 2 H), 1.28 (q, J=12.97 Hz, 2 H), 1.11-1.18 (m, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[C@@H:28]([C:29]([OH:31])=[O:30])[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:36]O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]3[C@@H:28]([C:29]([O:31][CH3:36])=[O:30])[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)(=[O:17])=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
77.5 g (177 mmol) of the carboxylic acid prepared in stage 1 were added in portions to a solution of 65 ml of thionyl chloride (885 mmol) in 800 ml of methanol at a temperature of −15° C. to −10° C. The mixture was then stirred at 25° C. for 1 hour and at 50° C. for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]#[N:22])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1>[NH4+].CO.[Ni]>[Cl:1][C:2]1[C:3]([CH2:21][NH2:22])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cccc2-c2cnc(C#N)c(Cl)c2)n1
Agent: [Ni]
Agent: [NH4+]
Solvent: CO
Product: Cn1nnc(-c2c(F)cccc2-c2cnc(CN)c(Cl)c2)n1
Reaction time: 3 h

Procedure:
To a solution of 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonitrile (0.500 g, 1.59 mmol) in ammonium in methanol (40 mL 2.0 M) was added Raney 2800 nickel (slurry in water). The reaction mixture was stirred under H2 atmosphere for 3 hours, filtered through glass filter paper and concentrated under vacuum. The residue was azeotroped three times with toluene to yield crude 1-{3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridin-2-yl}methanamine that gave a mass ion (ES+) of 319.18 for M+H+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O:14][CH2:15][C:16]([NH2:18])=[S:17])(=O)C.Cl>O1CCOCC1>[OH:14][CH2:15][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1
Reactant: CC(=O)OCC(N)=S
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: OCc1nc(-c2ccccc2)cs1
Reaction time: 0.5 h

Procedure:
2-Bromoacetophenone (39.9 g; 0.2 mole) and 2-acetoxythioacetamide (30 g; 0.225 mole) were dissolved in dioxan (150 ml). The mixture was stirred and heated on a steam bath for 15 minutes, yielding a mass of crystals. Aqueous 5N HCl (40 ml) was added and the heating continued for a further 30 minutes. The dioxan was evaporated under vacuum and the residue neutralised with aqueous Na2CO3 solution. The solid was collected, washed with water and dried. After recrystallisation from benzene the product weighed 33.5 g (87%) and had a m.p. of 88°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47]>O1CCCC1>[CH2:46]([N:48]([CH2:49][CH3:50])[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH:21]=[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=1)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH3:47]
Reactant: CCNCC
Reactant: O=C(O)CCCC=C(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCCC=C(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
1.0 g of 6-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid are dissolved in 15 ml of tetrahydrofuran and stirred for 15 minutes with 0.49 g of carbonyldiimidazole. Then 1 ml of diethylamine is added and the mixture is refluxed for 2 hours. It is then concentrated by evaporation and the residue is taken up in ethyl acetate and dried. Finally, it is chromatographed over a silica gel column using ethyl acetate as eluant.