Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[NH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:21]1([C:27](=[N:28][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
(S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (47 g, 137 mmol), diphenylmethanimine (29.9 g, 27.6 m, 165 mmol), BINAP (6.41 g, 10.3 mmol) and Pd2(dba)3 (3.14 g, 3.43 mmol) were dissolved under Argon in dry and de-aerated toluene (940 ml) and treated with sodium tert-butoxide (18.5 g, 192 mmol). The dark brown mixture was stirred at 90° C. for 18 h. The yellow/brown reaction mixture was diluted with toluene (700 ml), cooled to rt and extracted twice with water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was diluted with 300 ml hexane, stirred for 1 h and filtered off, leading to an orange solid (68 g) which was purified by column chromatography (1.3 Kg silicagel, 20% ethylacetate/heptane). The combined and concentrated fractions were suspended in hexane, stirred for 17 h, filtered off andf dried in high vacuo, to yield 54.1 g (89%) yellow solid. MS (ISP): 443.3 ([M+H]+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].Cl.[CH3:15][CH2:16][OH:17]>>[N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10](=[NH:11])[O:17][CH2:16][CH3:15])=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: CCO
Reactant: N#Cc1ccc(CCN=[N+]=[N-])cc1
Agent: Cl
Product: CCOC(=N)c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-azidoethyl)benzonitrile (2.0 g, 11.62 mmol) in EtOH (50 ml) at 0° C. was saturated with HCl(g). Reaction mixture was allowed to warm to room temperature and stirred overnight. Concentration of the crude reaction mixture gave ethyl 4-(2-azidoethyl)benzenecarboximidoate which was used without further purification.
Reaction SMILES: [Na+].[Br-].C([O-])(O)=O.[Na+].[C:8]1([CH2:14]/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[O-]Cl.[Na+]>C1(C)C=CC=CC=1.O>[C:8]1([CH2:14]/[C:15](/[CH3:19])=[CH:16]/[CH:17]=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: C/C(=C\CO)CC1=CCCCC1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C/C(=C\C=O)CC1=CCCCC1
Reaction time: 1 h
Yield: 66 %

Procedure:
NaBr (0.6 g, 0.006 mol) and NaHCO3 (6.4 g, 0.076 mol) were mixed together with water (60 ml), toluene (250 g) and (2E)-4-cyclohexenyl-3-methylbut-2-en-1-ol (96 g (0.573 mol, purity: 99% sum of the isomers) at room temperature with continuous stirring. NaOCl (13% w/w aqueous 426.8 g, 0.745 mol) was added to the reaction mass over 2 h. Stirring was continued for another 1 h. The aqueous phase was removed, organic phase was washed with a solution of NaHCO3 and then with water. The organic phase thus obtained was concentrated and crude product purified by fractional distillation to provide (2E)-4-cyclohexenyl-3-methylbut-2-enal (62.6 g, yield: 66%, GC purity: 95% sum of the isomers).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:45]=3)[C:40]2=[O:54])=[N:32][CH:33]=[CH:34][C:35]=1B(O)O)(=[O:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:51])([CH3:50])[CH3:52])[CH:45]=3)[C:40]2=[O:54])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 116d (175 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (300 mg, 0.75 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (150 mg, 1.0 mmol), and acetonitrile/water (20/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 116e as a yellow solid (150 mg, 45%). MS-ESI: [M+H]+ 683.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:55][C:56]([F:64])([F:63])[CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:60]3[CH2:61][CH2:62][CH:57]([C:56]([F:64])([F:63])[F:55])[CH2:58][CH2:59]3)=[O:40])=[CH:37][CH:38]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:29])[CH3:30])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.6 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.337 g, 0.545 mmol) in CH2Cl2 (20 mL) with 1,1′-carbonyldiimidazole (0.177 g, 1.09 mmol) and stir for 45 minutes at room temperature. Treat the reaction with 4-trifluoromethylpiperidine hydrochloride (0.155 g, 0.818 mmol) and diisopropylethylamine (0.106 g, 0.818 mmol) and stir for 12 hours at room temperature. Load the mixture on a silica gel column, flash with 25% to 50% ethyl acetate in hexanes to afford 0.34 g (84%) of the title compound. MS (m/z): 754 (M+).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.CCN(CC)CC.Cl>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH:2]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=C(C)CC(N)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OCC
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A solution of ethyl 2-amino-4-methyl-4-pentenoate (2.84 g, 18.1 mmol, prepared as in Reaction Scheme 19 from (benzhydrylideneamino)acetic acid ethyl ester and 1-bromo-2-methyl-2-propene) in CH2Cl2 (250 mL) was reacted with 4-chlorobenzenesulfonyl chloride (4.20 g, 19.9 mmol) and Et3N (3.78 mL, 27.2 mmol). After 4 h, the resulting mixture was poured into 1 N aqueous HCl (500 mL) and extracted with EtOAc (3×150 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude concentrate was purified using silica gel column chromatography (10:1 to 5:1 gradient, hexanes/EtOAc) to afford 3.04 g (25% yield over 3 steps) of ethyl 2-(4-chlorobenzenesulfonylamino)-4-methyl-4-pentenoate: LCMS (M+Na)+354.2; 1H NMR (400 MHz, CDCl3) 7.77 (d, 2H, J=9.1), 7.46 (d, 2H, J=8.8), 5.07 (d, 1H, J=9.0), 4.84 (s, 1H), 4.73 (s, 1H), 4.05 (m, 1H), 3.95 (q, 2H, J 7.1), 2.40 (m, 2H), 1.66 (s, 3H), 1.13 (t, 3H, J=7.1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[CH:7][N:6]=1)=O.O.[NH2:13][NH2:14]>CO>[Cl:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([NH:13][NH2:14])=[O:2])=[N:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: O
Solvent: CO
Product: NNC(=O)c1cnc(Cl)cn1

Procedure:
5-chloro-pyrazine-2-carboxylic acid methyl ester (10.02 g, 58.25 mmol) and hydrazine monohydrate (12.5 mL, 250 mmol) were dissolved in methanol (400 mL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title compound, 5.01 g (50%).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][N:23]3[CH:31]=[CH:32][CH:33]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1)=[O:10]>CN1CCCN(C)C1=O>[CH:33]1[CH:32]=[CH:31][N:23]2[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:20]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][N:2]4[CH:6]=[N:5][CH:4]=[N:3]4)=[CH:17][CH:16]=3)=[O:19])[CH2:21][C:22]=12
Reactant: c1nc[nH]n1
Reactant: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [Na]
Solvent: CN1CCCN(C)C1=O
Product: O=C(Cn1cncn1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is added 0.10 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone followed by stirring at room temperature for 3 hours. The reaction mixture is quenched with 15 ml of water and the resulting solid is collected, washed with water and hexanes to give 70 mg of the desired product as a tan solid. MS(CI): 413(M+H).
Reaction SMILES: [CH2:1](C(O)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([OH:17])(=[O:16])[CH2:14][OH:15].C(N(CC1C=CC=CC=1)C(=NC(C)C)O)(C)C>C1COCC1>[C:13]([O:17][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])[CH2:14][OH:15]
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: O=C(O)CO
Agent: CC(C)N=C(O)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: O=C(CO)OCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Construction of Benzyl-glycolic Acid. Glycolic acid (7.69,100 mmols) is added to N,N'-diisopropylbenzylisourea (23.39,100 mmols) with stirring for 1 hour. The volume is then increased to 200 mL with THF, and the mixture stirred for 48 h at room temperature. After cooling the mixture to -15° C., the diisopropylurea is removed by filtration and the THF evaporated under reduced pressure. The resulting product is pumped under high vacuum for 24 h to give benzyl glycolate which may be used without further purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:3])=[CH:35][CH:34]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(-c4nc5ccccc5s4)cc3)(CC1)CC2
Yield: 12.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(benzothiazol-2-yl)aniline (51.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-[4-(benzothiazol-2-yl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (10.4 mg).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:40])[CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)(C)CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 19 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-3,3-dimethylbutanamide according procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 10.73–10.50 (br, 1H), 8.63–8.48 (m, 1H), 7.97–7.77 (br, 1H), 7.70 (d, 1H, J=7.2 Hz), 7.45–7.11 (m, 11H), 6.89 (d, 1H, J=7.2 Hz), 5.01 (s, 1H), 3.46–3.26 (m, 4H), 2.97–2.77 (m, 2H), 2.77–2.50 (m, 3H), 2.42–2.17 (m, 2H), 2.25 (s, 2H), 2.14–1.94 (m, 2H), 1.93–1.78 (m, 2H), 1.00 (s, 9H); ESMS m/e: 526.4 (M+H)+; Anal. Calc. (HCl salt) C34H44ClN3O2.0.31CHCl3: C, 68.77; H, 7.45; N, 7.01. Found: C, 68.51; H, 7.40; N, 7.39.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[C:4]([F:11])[N:3]=1.[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:8][C:7]1[C:2]([O:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]#[N:13])=[N:3][C:4]([F:11])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: Cc1c(F)c(F)nc(F)c1F
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(F)c(F)nc(Oc2cccc(C#N)c2)c1F
Temperature: 45 °C

Procedure:
To 2,3,5,6-tetrafluoro-4-methylpyridine (0.71 g, 4.3 mmol) dissolved in acetonitrile (5 mL) was added 3-cyanophenol (0.5 g, 4.2 mmol) and cesium carbonate (1.44 g, 4.4 mmol). The reaction was heated in an oil bath at 45° C. for 16 hours and partitioned with ether and water. The organic layer was separated, washed with brine, dried (Na2SO4), and the solvent removed in vacuo. Chromatography on silica gel with methylene chloride/hexane (7/3) gave 3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)-oxy]benzonitrile; NMR (CDCl3) 7.55 (m,2), 7.45 (m,2), 2.24 (s,3) ppm.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccnc1C(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccnc1C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-methylpyridine (4.0 g) and sodium azide (6.7 g) in DMSO (80 ml) was stirred for 21 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.90 g) in THF (40 ml) was added dropwise to a suspension of aluminum lithium hydride (1.24 g) in THF (40 ml) at 0° C. The mixture was stirred at room temperature for 3 hours, water (1.24 ml), 15% aqueous solution of sodium hydroxide (1.24 ml) and water (3.72 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred temperature for 16 hours at room temperature, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, to give (4-aminophenyl)(3-methylpyridin-2-yl)methanol (2.60 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[N:13]=2)=[CH:4][C:3]=1[O:24][CH3:25].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.[F-].[K+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][C:11]3[CH2:17][CH2:16][CH2:15][CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:30]1[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=1
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: CO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1cnn(C)c1
Yield: 15.8 %

Procedure:
In a microwave vial a mixture of (4-bromo-3-methoxy-phenyl)-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine (120 mg, 0.289 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (185 mg, 0.88 mmol), palladium (II) acetate (6 mg 0.027 mmol) and potassium fluoride (51 mg, 0.867 mmol) in 6 ml methanol was purged with nitrogen. The vial was sealed and the mixture was irradiated for ½ h at 140° C. in a microwave oven. The reaction mixture was filtered and the filtrate was concentrated, the residue was dissolved in dichloromethane, washed three times with water, dried and evaporated in vacuo. Column chromatography (12 g silica, dichloromethane+1.8% methanol v/v) afforded the title compound (19 mg, 16%) as a light brown wax. MS ISP (m/e): 417.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.79 (s, 1H), 7.75 (s, 1H), 7.38 (d, 1H), 7.22 (m, 6H), 6.97 (s, broad, 1H), 6.65 (dd, 1H), 4.05 (s broad, 1H), 3.92 (s, 3H), 3.68 (s, 3H), 2.75 (m broad, 2H), 2.20 (m broad, 1H), 1.88 (m broad, 3H).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CS(C)=O>[CH3:1][NH:2][C:4]1[CH:5]=[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1F
Solvent: CS(C)=O
Product: CNc1cc(CN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
An aqueous solution of methylamine (40 wt %, 910 ml) at 30° C. is added to a 61° C. solution of 4-(3-fluoro-4-nitrobenzyl)morpholine (504 g) in DMSO (810 ml) followed by a DMSO rinse (150 ml) over ½ h. The mixture is allowed to reflux at 47 ° C. over 5 min then maintained at <51° C. by occasional ice bath cooling for remainder of the addition. The mixture is stirred at 50° C. for ¾ h and then water (2000 ml) is added. The mixture is cooled to 0° C. and the precipitate is collected by filtration, washed with water (1500 ml) and is dried in a nitrogen stream to give a bright orange solid (529 g). Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ2.35, 2.93, 3.44, 3.56, 6.63, 6.64, 7.78, 8.15; 13C NMR (100 MHz, DMSO-d6) δ29.95, 53.57, 62.27,66.54, 113.69, 115.76, 126.49, 130.16, 146.27, 148.07.
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)/[C:4](OCC)=[O:5].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O.CO>[F:1]/[CH:2]=[C:3](\[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)/[CH2:4][OH:5]
Reactant: CCOC(=O)/C(=C/F)CCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: -15 °C
Reaction time: 18 h

Procedure:
Combine ethyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate (1.5 g, 6.24 mmol) and toluene (5 mL). Cool to -15° C. Add dropwise, a solution of diisobutylaluminum hydride (10.4 mL, 1.5M in toluene, 15.6 mmol). Warm to ambient temperature. After 18 hours, cool to 0° C. With vigorous stirring add sequentially, methanol (15 mL), an aqueous 5M hydrochloric acid solution (25 mL), and water (35 mL). When gas evolution ceases, extract with toluene. Separate the layers and evaporate organic layer in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.28 (s, 1H), 2.45 (m, 2H), 2.72 (m, 2H) 3.91 (d, J=3Hz, 2H), 6.57 (d, J=87Hz, 1H), 6.96 (m, 2H), 7.13 (m, 2H).
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C=CC=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.[CH:36]1([N:40]([CH2:70][CH2:71]O)[C:41]([C:43]2[C:48]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[C:47]([OH:57])[N:46]=[C:45]([CH2:58][C:59]3([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[CH2:63][CH2:62][CH2:61][CH2:60]3)[N:44]=2)=[O:42])[CH2:39][CH2:38][CH2:37]1>>[CH2:50]([O:49][C:48]1[C:47](=[O:57])[N:46]=[C:45]([CH2:58][C:59]2([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:63][CH2:62][CH2:61][CH2:60]2)[N:44]2[CH2:71][CH2:70][N:40]([CH:36]3[CH2:39][CH2:38][CH2:37]3)[C:41](=[O:42])[C:43]=12)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCC1
Yield: 38.1 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclobutyl-(2-hydroxyethyl)-amide (293) (100 mg, 0.19 mmol). The product was obtained as a white solid (35 mg, 36.3%).
Reaction SMILES: [N+](=C)=[N-].C1(C2C=CC=CC=2)C=CC=CC=1.[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[O:24]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CCCCC(=O)O
Agent: C=[N+]=[N-]
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=CCCCCC(=O)O
Yield: 18 %

Procedure:
After the reaction, the autoclave was cooled with ice, and the pressure was reduced; subsequently, the contents were treated with diazomethane, and the reaction mixture was analyzed by gas chromatography using biphenyl as an internal standard. The results confirmed that adipic acid was obtained in a yield of 38%, and 6-oxohexanoic acid was obtained in a yield of 18%. With regard to the products, the reaction mixture was analyzed by FT-NMR using coumarin as an internal standard, and the results confirmed that adipaldehyde was obtained in a yield of 42%, and adipic acid was obtained in a yield of 19%.