Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:18][CH:17]2[C:36]([OH:38])=O)[CH:12]=[CH:13][C:14]=1[F:15].[NH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][O:46][C:44](=[O:45])[C:43]1[CH:48]=[CH:49][C:40]([NH:39][C:36]([C@H:17]2[C@H:16]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([Cl:8])[CH:10]=3)[C@:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[C@H:19]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:18]2)=[O:38])=[CH:41][CH:42]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(F)c(Cl)c2)cc1
Yield: 48.4 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.25 g, 0.43 mmol) was reacted with methyl 4-aminobenzoate (0.12 g, 0.8 mmol), HATU (0.29 g, 0.43 mmol) and iPr2NEt (0.19 mL, 1.1 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.125 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[Cl:11].C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[Cl:11]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: N=CN
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(Cl)c1Cl
Reaction time: 1 h

Procedure:
48.0 g of 1,2-dichloro-3-nitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 12 bar and a temperature of 80° C. The hydrogenation time is 1 hour. 1,2-Dichloro-3-aminobenzene, 99.7% pure (analysed by gas chromatography), is obtained in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH2:10][C:11]2([OH:19])[C:16]([OH:18])=[O:17])=[O:4].[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CN(C)C=O.S(Cl)(Cl)=O>C(#N)C>[F:1][C:2]([F:20])([F:21])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH2:10][C:11]2([OH:19])[C:16]([O:18][C:24]1[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)=[O:17])=[O:4]
Reactant: O=C(Nc1cccc2c1C=CCC2(O)C(=O)O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1cccc2c1C=CCC2(O)C(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 82 %

Procedure:
In 1.5 liters of acetonitrile were dispersed 200 g of 5-trifluoroacetamido-1-hydroxynaphthoic acid and 100 g of p-nitrophenol, and the mixture was stirred under heating. To the dispersion was added 15 ml of dimethylformamide, and 110 ml of thionyl chloride was added thereto dropwise. After the dropwise addition, the mixture was heated while stirring for 1 hour, followed by cooling. The precipitate thus formed was collected by filtration, washed with acetonitrile, and dried to obtain 230 g of p-nitrophenyl 5-trifluoroacetamido-1-hydroxynaphthoate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C=O)C.[O:42]1[CH2:47][CH2:46][CH:45]([C:48](Cl)=[O:49])[CH2:44][CH2:43]1>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:48]([CH:45]5[CH2:46][CH2:47][O:42][CH2:43][CH2:44]5)=[O:49])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(Cl)C1CCOCC1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)C1CCOCC1)C2
Temperature: 25 °C

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) (100 mg, 0.37 mmol) and triethyamine (42.4 μL, 0.30 mmol) in DCM (3 mL, anhydrous), and DMF (1 mL, anhydrous) was added tetrahydro-2H-pyran-4-carbonyl chloride (45.2 mg, 0.30 mmol). The reaction mixture was stirred at room temperature until LCMS indicated reaction was complete. Solvent was then removed in vacuo.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH:22]1[CH2:28][CH2:27][CH2:26][C:25]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23]1)[CH2:11][C@H:12]([OH:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.O>[CH2:3]([N:10]([CH:22]1[CH2:28][CH2:27][CH2:26][C:25]2[C:29]([O:33][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23]1)[CH2:11][C@H:12]([OH:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A suspension of 60% sodium hydride (54 mg, washed with n-hexane) in N,N-dimethylformamide (1 ml) was added slowly to a stirred solution of (2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (512 mg) in N,N-dimethylformamide (5 ml) under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. A solution of ethyl bromoacetate (225 mg) in N,N-dimethylformamide (1 ml) was added dropwise therein at the same temperature and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo to afford (2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.59 g) as a crude oil.
Reaction SMILES: O[CH2:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1.Br[CH2:17][C:18]#[C:19]C.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH2:2]([N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCBr
Reactant: NC(=O)c1ncn2c(=O)n(CO)nnc12
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC#CCn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 3-(Hydroxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-][1,2,3,5]tetrazine-8-carboxamide (MM-001) (1 equiv) in acetonitrile (0.17 M concentration substrate in solvent) was added the 1-bromo-2-butyne (4 equivs) and DBU (1.4 equivs). The mixture was stirred at this temperature for 30 minutes whereupon it was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×1 reaction volume). The combined organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oily residue which was then precipitated from Et2O and washed with further Et2O to give the title compound. 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.84 (1H, s), 7.82 (1H, s), 7.70 (1H, s), 5.08 (2H, q, J=2.4 Hz), 1.84 (3H, t, J=2.4 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](O)C2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 60 mg, 0.134 mmol) and (6-methylpyridin-3-yl)boronic acid (36.8 mg, 0.19 mmol) were dissolved in DME (0.5 mL). A solution of 2 M aq. NaHCO3 (0.2 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and then treated with Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol). The RM was stirred under argon at 90° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.09 min, UPLC-MS (Condition 7) m/z=459.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.75 (m, 1H) 1.76-1.87 (m, 1H) 2.52 (s, 3H) 2.86 (d, J=11.73 Hz, 1H) 3.11-3.24 (m, 2H) 3.27-3.43 (m, 1H) 4.17 (br. s, br. s, 1H) 4.83 (br. s, br. s, 1H) 7.28-7.39 (m, 3H) 7.69 (dd, J=7.82, 1.96 Hz, 1H) 7.79-7.89 (m, 2H) 7.98 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:28]2=[O:30])=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(CNc1ccc(Br)cc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Yield: 151.2 %

Procedure:
A solution containing 2-(4-bromoanilino)-1-phenyl-1-ethanol (0.74 g, 0.00253 mol), N,N-diisopropylethylamine (1.01 g, 0.00786 mol) and N,N-dimethylaminopyridine (0.092 g, 0.00076 mol) in anhydrous dichloromethane (32 mL) was cooled to 0° C. and a solution of triphosgene (0.38 g, 0.00127 mol) in anhydrous dichloromethane (8 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for eighteen hours. The organic phase was washed with a saturated solution of sodium bicarbonate in water (40 mL), brine (30 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 3-(4-bromophenyl)-5-phenyl-1,3-oxazolan-2-one (0.62 g, 0.00192 mol) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].[Br:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C>[Br:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: c1ccc2c(c1)NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2CCOc3ccccc32)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a flask under nitrogen, 3,4-dihydro-2H-benzo[b][1,4]oxazine (Tyger Scientific Inc., Ewing, N.J., 0.457 mL, 3.70 mmol) was dissolved in DMF (18.50 mL) and at room temperature, NaH (60% dispersion in mineral oil) (0.326 g, 8.14 mmol) was added, and the reaction was stirred for 15 minutes. 2-Bromo-1-fluoro-4-(trifluoromethyl)benzene (Alfa Aesar, Ward Hill, Mass., 0.790 mL, 5.55 mmol) was then added, and the reaction was stirred overnight at room temperature until complete conversion to the desired product. The reaction was then quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (×2). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give material, which was purified via silica gel MPLC (Biotage Isolera One; PuriFlash HP, 15μ, 25 g (Biotage, Uppsala, Sweden)), eluting with 0 to 100% ethyl acetate in heptanes. Fractions containing clean product were collected and concentrated under a vacuum to yield 1.73 g of 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (INTERMEDIATE B) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.62-3.69 (m, 2H) 4.28 (t, J=4.21 Hz, 2H) 6.30 (dd, J=7.87, 1.71 Hz, 1 H) 6.71 (dtd, J=18.67, 7.42, 7.42, 1.71 Hz, 2H) 6.85 (dd, J=7.78, 1.81 Hz, 1 H) 7.59 (d, J=8.41 Hz, 1 H) 7.81 (dd, J=8.41, 1.56 Hz, 1 H) 8.13 (d, J=1.66 Hz, 1 H). m/z (ESI) 357.0 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([NH:20][CH2:21][C:22]([OH:24])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:25]1([CH:31]2[NH:36][CH2:35][CH2:34][N:33]3[CH:37]=[CH:38][CH:39]=[C:32]23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[N-]1C=CN=C1.C(NCC(O)=O)(OC(C)(C)C)=O>ClCCCl>[O:24]=[C:22]([N:36]1[CH2:35][CH2:34][N:33]2[CH:37]=[CH:38][CH:39]=[C:32]2[CH:31]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc(C2NCCn3cccc32)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCn2cccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 61.2 %

Procedure:
(1.1 g, 7.0 mmol) of CDI were added to a solution of Boc-glycine (1.2 g, 6.7 mmol) in DCE (20 ml), and stirring was carried out for 100 min at RT. (1.3 g, 6.7 mmol) of 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A2) were then added, and stirring was carried out for a further 2 h at RT. The mixture was then heated for 2 h at 50° C. (450 mg, 2 mmol) of Boc-glycine imidazolide were subsequently added, and the mixture was heated for 2 h under reflux. After cooling to RT, washing was carried out with, in succession, a 5% aq. sodium carbonate solution, a 5% aq. citric acid solution, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (DCE) with the residue yielded 1.4 g (4.1 mmol, 61%) of tert-butyl 2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethylcarbamate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:15])[CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[N:30][C:31]([Cl:37])=[CH:32][CH:33]=2)[N:28]=1.Cl>CN(C)C=O.O>[Cl:37][C:31]1[N:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27]([N:18]3[C:19](=[O:26])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]3[CH:8]([C:7](=[O:14])[CH2:6][CH2:5][C:4]([CH3:3])=[CH2:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:28]2)=[CH:33][CH:32]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: C=C(C)CCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCC(=O)C(C(=O)OCC)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.7 g of an oily suspension (50% by weight) of sodium hydride are added to 100 cm3 of anhydrous dimethylformamide, under an argon atmosphere, at a temperature of about 10° C. 9.8 g of ethyl 6-methyl-3-oxo-6-heptenoate in 25 cm3 of anhydrous dimethylformamide are subsequently added. The suspension is stirred for 30 minutes and the temperature is allowed to return to about 20° C., followed by the addition of 11.6 g of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone. The reaction mixture is stirred for 4 hours at a temperature of about 20° C. and is then poured into 250 cm3 of water. The aqueous phase, which is acidified by the addition of 25 cm3 of aqueous 1N hydrochloric acid solution, is extracted twice with 200 cm3 of dichloromethane. The organic phases are combined and washed twice with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue is purified by chromatography on silica [eluent:ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After crystallization in diisopropyl ether, 9.4 g of ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxo-6-heptenoate (mixture of A and B forms) are thus obtained, melting at 125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]#N)=[CH:8][C:7]=1[F:15].[CH3:20][CH2:21][OH:22].S(=O)(=O)(O)[OH:24]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:22][CH2:21][CH3:20])=[O:24])=[CH:8][C:7]=1[F:15]
Reactant: N#CCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CCO
Reactant: O=S(=O)(O)O
Product: CCOC(=O)Cc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To 2-(6-(3,4-difluorophenoxy)-5-fluoropyridin-3-yl)acetonitrile (3 g, 9.99 mmol) and EtOH (30 ml, 514 mmol) was added 18 M sulfuric acid (10 ml, 180 mmol). The reaction mixture was stirred at 80° C. for 2 hr., and then was concentrated under reduced pressure. To the residue was added 50 mL of concentrated ammonia solution and 100 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4, and then concentrated under reduced pressure to give ethyl 2-(6-(3,4-difluorophenoxy)-5-fluoropyridin-3-yl)acetate (3.1 g, 67.8%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30]Br)[N:25]=2)[N:20]=1.CO>C1COCC1>[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30][N:15]3[C:16]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[O:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:25]=2)[N:20]=1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(N)c2nc(CN3c4ccccc4Oc4ccccc43)cnc2n1
Reaction time: 0.17 h

Procedure:
NaH (60% oil suspension containing 51 mg, 2.0 mmol) was added to a stirred solution of phenoxazine (147 mg, 0.784 mmol) in dry THF (10 mL) at 0° C. under N2. After 10 min. 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.392 mmol) was added and the reaction mixture was allowed to come to room temperature and left to stir for 2 days. The excess NaH was decomposed with MeOH (1 mL), and the mixture was concentrated to dryness by rotary evaporation. Flash chromatography on silica gel yielded the title compound, N-[(2,4-diaminopteridin-6-yl)methyl]phenoxazine, as a brown solid; yield 47 mg (34%); mp >250° C. dec. Anal. Calcd. for C19H15N7O0.4H2O: C, 62.60; H, 4.37. Found: C, 62.84; H, 4.10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N+:16]([O-])=O)(O)[CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:20].[NH4+]>C1COCC1.CO.[Pd].CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:20])[CH:12]([NH2:16])[CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: CCC(O)(Cc1ccc(C(=O)OC)cc1)[N+](=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CCC(N)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 1-(4-methoxycarbonylphenyl)-2-nitro-butan-2-ol (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added 10% palladium on carbon (50 mg) followed by ammonium formate (0.4 g, 5 equivalents). The resulting mixture was stirred at room temperature for 3 hours ten diluted with Et2O, filtered and evaporated in vacuo. Flash column chromatography (SiO2, 15% MeOH in CHCl3) gave erythro 1-(4-methoxycarbonylphenyl)-2-amino-butan-1-ol (0.22 g, 73%).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Cl:14][C:15]1[CH:16]=[C:17]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([O:36][CH3:37])[N:30]=2)=[O:28])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].[Cl-].[NH4+]>CN(C)C=O>[Si:5]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([O:36][CH3:37])[N:30]=2)=[O:28])=[CH:16][C:15]=1[Cl:14])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1nc(C(=O)c2ccc(OCCCCO)c(Cl)c2)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1nc(C(=O)c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
tert-Butyldimethylchlorosilane (240 mg) and imidazole (108 mg) were sequentially added to a solution of [3-chloro-4-(4-hydroxybutoxy)phenyl](5-chloro-6-methoxypyridin-2-yl)methanone (391 mg) in N,N-dimethylformamide (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→10:1) to give the title compound (389 mg, 76%).