Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[F:6][C:7]([F:21])([F:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[Br:1][CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([F:20])([F:21])[F:6])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cc1ccccc1C(F)(F)F
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Br)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
585 mg (3.89 mmol) of sodium bromate were initially charged in 2 ml of water, and 300 mg (1.29 mmol) of ethyl 2-(trifluoromethyl)phenylacetate, dissolved in 2.5 ml of ethyl acetate, were added at RT. A solution of 403 mg (3.89 mmol) of sodium bisulfite in 3.8 ml of water was then added slowly. The mixture was stirred at RT for 18 h. 5 ml of 10% strength aqueous sodium dithionite solution were then added. The mixture was extracted with 15 ml of ethyl acetate, and the organic phase was washed in each case once with 5 ml of 10% strength sodium dithionite solution and 5 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 186 mg of a mixture consisting of the title compound and the starting material ethyl 2-(trifluoromethyl)phenylacetate (ratio 16:84 according to GC/MS [Method 20]). This mixture was once more reacted with 362 mg (2.40 mmol) of sodium bromate and 250 mg (2.40 mmol) of sodium bisulfite according to the procedure described above. Work-up gave a mixture of 31% title compound and 69% ethyl 2-(trifluoromethyl)phenylacetate, which was reacted further without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)=[O:29])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)C1CCOCC1
Product: Cc1ccc(NC(=O)C2CCOCC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)tetrahydropyran-4- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and tetrahydropyran-4-carboxylic acid using method D. NMR; δH [2H6]—DMSO 9.89,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.52-7.48,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.89,(2H, m), 3.37,(1H, m), 3.16,(2H, t), 2.56,(2H, m), 2.16,(3H, s), 1.65,(3H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.94 min, MH+393.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[C:19]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]2[CH3:38])[CH:26]=1)([CH3:22])([CH3:21])[CH3:20].[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=1[F:50].C(N(CC)CC)C>ClCCl>[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([NH:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:39])[C@H:33]([CH3:38])[CH2:34]2)=[O:46])=[CH:43][C:42]=1[F:50]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: C[C@@H]1CNCCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.967 g, 3 mmol, 1.840 mL, 50% solution in ethyl acetate) was added dropwise to a solution of (R)N-tert-butyl-3-((2-methylpiperazin-1-yl)methyl)benzamide (500 mg, 1.7 mmol), 4-amino-3-fluorobenzoic acid (239.7 mg, 1.5 mmol) and triethylamine (469 mg, 4.5 mmol, 1.84 mL) in dichloromethane. The reaction was stirred at room temperature for 2 hours. The dichloromethane was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic layer was concentrated under vacuum to afford the title compound (476.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccccn1)C1(c2ccc(Cl)cc2)CC1
Product: O=[N+]([O-])c1cc(C2(Cc3ccccn3)CC2)ccc1Cl

Procedure:
Prepared analogously to Example 231c from [1-(4-chlorophenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone and fuming nitric acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C.CCCCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]=[N+:2]=[N-:3])[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCCCCBr
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN=[N+]=[N-]
Reaction time: 16 h
Yield: 95.1 %

Procedure:
Sodium azide (1.7 g, 0.026 mol) was added to ethyl 7-bromoheptanoate 1 (4.1 g, 0.017 mol) in DMF (40 mL) at 23° C. The reaction was stirred for 16 h, diluted with pentane and washed with water. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 3.22 g (95%) of the azide 2 as a clear, colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH:20]1([CH:25]([OH:28])[C:26]#[CH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:27]#[C:26][CH:25]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[OH:28])[N:5]=2
Reactant: C#CC(O)C1CCCC1
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(O)C3CCCC3)nc21

Procedure:
A suspension of 1 g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 25 ml of a dimethylformamide/triethylamine mixture (V/V; 2.5/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.931 g (7.5 mmol) of (±)-1-cyclopentylprop-2-yn-1-ol, 0.068 g of CuI (0.36 mmol) and 0.125 g of bis(triphenylphosphine) palladium(II)dichloride (0.18 mmol) are successively added.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([N:24]1[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1coc(=O)c2ccc(Br)cc12
Solvent: CO
Product: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12

Procedure:
A mixture of the product of Example 37 step ii) (5 g) and benzylamine (3 mL) in methanol (20 mL) was heated at reflux for 40 hours. The reaction was concentrated to half volume, then treated with acetonitrile. The sub-title compound was collected by filtration, washing with acetonitrile (5.30 g).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)[CH3:6])[CH3:2].[H-].[Na+].Br[CH:31](C)C>CN(C=O)C.O>[CH:1]([O:3][N:4]=[C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)[CH3:6])([CH3:31])[CH3:2]
Reactant: CCON=C(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NOC(C)C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a suspension of 33i (Example 14) (0.4 g, 1.22 mmol) in dry DMF (5 ml) is added sodium hydride (50 mg of a 60% dispersion in mineral oil). The mixture is stirred at 30-40° C. for 30 min. 2-Bromopropane (0.14 ml, 1.49 mmol) is added and the mixture is stirred at 40° C. over night. After cooling the mixture is diluted with 4 volumes of water and extracted with dichloromethane. The organic extract is concentrated and eluted through silica gel with ethyl acetate to yield 0.15 g 33j (33%). Mp 77-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][CH2:19]Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][CH2:17][O:18][CH3:19])[N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.32 g (7.54 mmol) of [2-(4-chlorophenyl)-1,3-oxazol-4-yl]methanol (Example 100A) are initially charged in 18.5 ml of dry THF and cooled to 0° C., and 0.33 g (8.29 mmol) sodium hydride (60% strength in mineral oil) are added. The mixture is stirred at 0° C. for 10 min and then at RT for 1 h. The reaction mixture is again cooled to 0° C., and 0.69 ml (9.04 mmol) of chlorodimethyl ether is added. The mixture is stirred at 0° C. for 10 min and then at RT for 2 h. 5 ml of water are then added, and the reaction mixture is extracted three times with in each case 25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)[CH3:9].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1ccccc1
Yield: 78.6 %

Procedure:
A mechanically stirred mixture of aniline (71 g; 0.76 mol), ethylbromoacetate (127.5 g; 0.76 mol), and anhydrous sodium acetate (62.6 g; 0.76 mol) in absolute ethanol (10 mL) was heated at reflux for 6 hours. The mixture was cooled, water was added to precipitate the product, and the solid was filtered and dried. The crude product was crystallized from ethanol-water to give N-phenylglycine ethyl ester (107 g; 79%) having amp 48°-49° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[C:20]([CH3:22])[C:18](=[O:19])[NH:17][C:15]1=[S:16].C(N(CC)CC)C.[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33]>CO>[F:30][C:31]([F:38])([F:37])[C:32]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[C:20]([CH3:22])[C:18](=[O:19])[NH:17][C:15]1=[S:16])=[O:33]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN)c(=S)[nH]c1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCNC(=O)C(F)(F)F)c(=S)[nH]c1=O

Procedure:
2′-O-Aminopropyl-5-methyl-2-thiouridine is dissolved in MeOH and 5 equivalents of triethylamine are added followed by 10 equivalents of ethyl trifluoroacetate. The title compound is isolated after purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:29]O)[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:29][NH:17][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:16][CH:15]=3)[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCCN2CCCCC2)cc1
Yield: 58.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Piperidin-1-yl-propoxy)-phenylamine (0.61 g, 1.3 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.358 g, 2.00 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (465 mg, 59%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.O1CCCC1.[H-].[Na+]>O>[CH2:1]([C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Oc1ccc(I)cc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(I)cc1Cc1ccccc1

Procedure:
10.1 g of 2-benzyl-1-hydroxy-4-iodobenzene and 3 ml of chloromethyl methyl ether were added to 100 ml of tetrahydrofuran and while stirring on an ice bath, 1.45 g of 60% (oily) sodium hydride was added dropwise to the mixture. After stirring for 2 hours, water was added to the reaction mixture, which then was extracted with ethyl acetate, washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography with 10% ethyl acetate/hexane, to give 8.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.[F:63][C:64]([F:72])([F:71])[CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:23][C:6]1[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:68]3[CH2:69][CH2:70][CH:65]([C:64]([F:72])([F:71])[F:63])[CH2:66][CH2:67]3)=[O:31])=[CH:26][CH:25]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix 3′,5′-dichloro-4′-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.350 g, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216 g, 1.11 mmol), N-methylmorpholine (0.33 mL, 2.95 mmol), hydroxybenzotriazole (0.247 g, 0.74 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.226 g, 1.47 mmol) in CH2Cl2 (10 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate brine. Dry over magnesium sulfate, filter, and concentrate under vacuum. Purify by flash column chromatography to recover 0.350 g (78%) of the title compound: MS (m/z): 611 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]3[C:21](=[N:22][CH:23]=2)[N:20]=CN(C)[C:17]3=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[N:22][C:21]([NH2:20])=[C:16]([C:17]([OH:25])=[O:26])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cnc2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a stirred suspension of 4-(3-methyl-4-oxo-3,4-dihydro-pteridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (428 mg, 1.24 mmol; see Example 16 (d) above) in methanol (5 mL) was added 10% aqueous sodium hydroxide (5 mL). The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was then diluted with water and neutralized with formic acid (pH 7). The resulting precipitate was removed by filtration and the filtrate was acidified with formic acid (pH 4) and extracted with methylene chloride. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4tert-butyl ester as a yellow solid (265 mg, 67%). 1H NMR (300 MHz, CDCl3) δ1.49 (s, 9 H), 3.38 (t, J=5.4 Hz, 4H), 3.60 (t, J=5.4 Hz, 4H), 6.06 (br s, 1H), 8.15 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ28.39, 46.16, 80.29, 116.40, 138.73, 147.39, 149.67, 154.59, 165.95.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (7.2 g, 34.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.37 g, 34.3 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 1-(chloromethyl)-3-(phenyloxy)benzene (9.0 g, 41.6 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was heated under reflux overnight. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((3-(phenyloxy)phenyl)methyl)propionate (10.2 g, crude, 76%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26]([C:32](=[O:34])[CH3:33])[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(Cc3ccccc3F)c2C1
Yield: 12 %

Procedure:
1-(4-(2-Fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12 mg, 12%) was prepared from 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 457 (M+H)+
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(Cc2ccc(I)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Yield: 794.3 %

Procedure:
To a mixture of 1-(4-iodobenzyl)-4-methoxybenzene (0.300 g, 0.925 mmol), 2N aqueous NaHCO3 solution (1.85 mL, 3.7 mmol), and 2-thiopheneboronic acid (0.237 g, 1.85 mmol) in a solution of toluene/EtOH (17.6/0.8 mL) at ambient temperature under an atmosphere of nitrogen was added tetrakis(triphenylphosphine)palladium(0) (0.107 g, 0.093 mmol). The procedure in Example 15, Step 1 was followed to give the title product as a white solid (2.06 g, 79%): 1H NMR (400 MHz, CDCl3): δ 7.52 (d, 2H, J=8.4 Hz), 7.25 (m, 2H), 7.18 (d, 2H, J=8.4 Hz), 7.11 (d, 2H, J=8.8 Hz), 7.05 (m, 1H), 6.84 (d, 2H, J=8.8 Hz), 3.93 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]([CH3:36])([CH3:35])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH3:35][C:11]1([CH3:36])[C:12]2[C:17](=[CH:16][C:15]([CH:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10]1
Reactant: CCCCCC(C#Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC(C#Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)NCCC2(C)C
Yield: 73.3 %

Procedure:
A solution of 7-[3-(4-carboxy-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.035 g, 0.07 mmole) in 2 mL of a 1:1 TFA/dichloromethane mixture was stirred for 30 minutes and concentrated. The residue was dissolved in 5 mL of dichloromethane and washed with 5 ml of saturated sodium bicarbonate, 5 mL of water and 5 mL of brine, the organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 0.02 g of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-ynyl]-benzoic acid as brownish oil. MS (ESI): (M−): 388.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])([CH3:1])(=[O:4])=[O:3]
Reactant: CC(=O)CCCCC=CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CCCCC=CCOS(C)(=O)=O
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Methane sulphonylchloride (8.07 g; 1.1 eq) was added dropwise over 30 minutes to a stirred solution of 9-hydroxy-non-7-en-2-one (10 g) in dry dichloromethane (60 ml) containing an excess of triethylamine (9.71 g; 1.5 eq), at -10° C. The solution was stirred for a further 20 minutes. The reaction mixture was washed with cold water, cold 5 N hydrochloric acid, cold 5% sodium bicarbonate solution and cold brine then was dried and evaporated in vacuo at <30° to give 9-mesyloxy-non-7-en-2-one (12.7 g) as a deep red oil.