Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[C:9]=1[F:16]>C(O)(=O)C>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]([OH:14])=[C:10]([F:15])[C:9]=1[F:16]
Reactant: COC(=O)c1ccc(O)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(O)c(F)c1F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Concentrated nitric acid (70% w/w) (0.72 mL, 11.2 mmol) in glacial acetic acid (2 mL) was added dropwise to a solution of 2,3-difluoro-4-hydroxy-benzoic acid methyl ester [Gonzales, Javier et al., PCT Int. Appl. (1999), 551 pp. WO 9901423 A1 19990114] (2 g, 10.6 mmol) in glacial acetic acid (28 mL). The mixture was stirred at 45° C. for 0.5 hour and then at room temperature overnight before it was evaporated to a quarter of the volume in vacuo. Water was added to the concentrate to give a solid precipitate which was filtered, washed with water twice and dried to give the title compound (2.2 g, 88%) as a colourless solid.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:38])[C@@H:16]2[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([NH:55][C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[O:49])[CH2:43]1>>[N+:66]([C:63]1[CH:62]=[CH:61][C:60]([CH2:59][O:58][C:56]([NH:55][C@H:52]2[CH2:53][CH2:54][N:50]([C:48]([C@H:44]3[N:45]([CH3:47])[CH2:46][C@@H:42]([S:41][C:14]4[C@H:15]([CH3:38])[C@@H:16]5[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:43]3)=[O:49])[CH2:51]2)=[O:57])=[CH:65][CH:64]=1)([O-:68])=[O:67]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 27(b), but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared as described in Example 27(a)] and (2S,4S)-4-mercapto-2-[3(S)-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-yl-carbonyl]-1-methylpyrrolidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a powder in a yield of 60%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2ccc(CC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.89 g), methyl 2-(4-hydroxyphenyl)acetate (0.50 g), anhydrous potassium carbonate (0.49 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained crystal, tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.13 g, 93%) of 2-[4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 179-180° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]1([CH2:22][NH2:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:23][CH2:22][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (3.86 g, 20 mmol), naphthalen-1-ylmethanamine (3.14 g, 20 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (100 mL) was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (500 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet ether=1/6 to afford the desired product as a yellow solid (3.21 g, 51%); LC/MS: MS (ES+) m/e 314 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 5.21 (d, J=6.0 Hz, 2H), 6.80 (d, J=8.7 Hz, 1H), 7.43-7.63 (m, 4H), 7.85 (d, J=8.1 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 9.20 (t, J=5.7 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.Cl[C:12]1[C:21]([C:22]2[CH:27]=[C:26]([S:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=2)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)C.N>Cl.CO.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:12]3[C:21]([C:22]4[CH:27]=[C:26]([S:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=4)=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CSc1cc(-c2nc3ccccc3nc2Cl)nc(C)n1
Reactant: Nc1cccc2[nH]ncc12
Agent: Cl
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CSc1cc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)nc(C)n1
Temperature: 160 °C
Yield: 45.4 %

Procedure:
A glass microwave reaction vessel was charged with 1H-indazol-4-amine (220 mg, 1.651 mmol, Key Organics Limited/Bionet Research, United Kingdom), 1 drop of concentrated HCl, 2-chloro-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxaline (250mg, 0.826 mmol), and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 1 h. The mixture was cooled to room temperature, then neutralized by 2 N NH3 in MeOH, diluted with DCM and filterd through a Celite® (diatomaceous earth). The filtrate was concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to10% 2 M NH3.MeOH in DCM to give N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxalin-2-amine (150 mg, 0.375 mmol, 45.5% yield) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.23 (s, 1H); 12.59 (s, 1H); 8.50 (d, J=7.63 Hz, 1H); 8.42 (s, 1H); 8.31 (s, 1H); 8.03 (d, J=8.22 Hz, 1H); 7.74-7.85 (m, 2H); 7.59 (t, J=7.43 Hz, 1H); 7.41 (t, J=7.92 Hz, 1H); 7.27 (d, J=8.22 Hz, 1H); 2.91 (s, 3H); 2.68 (s, 3H). m/z (ESI, +ve ion) 400 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].[OH:28][NH2:29].[OH-].[K+]>ClCCl>[OH:28][NH:29][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:24]([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)(=[O:26])=[O:25])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: NO
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 3,4-dichlorobenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 415, exp (MH+) 415.3. 1H NMR (CD3OD, 400 MHz), 8.05 (d, 1H, J=2.0 Hz), 7.82 (dd, 1H, J1=8.4 Hz, J2=2.0 Hz), 7.76 (d, 1H, J=8.4 Hz), 7.46 (d, 1H, J=8.0 Hz), 7.33 (s, 1H), 7.14 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>O1CCCC1O>[C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: OC1CCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-nonanoyl tyramine was prepared by adding dropwise about 2.74 moles of nonanoyl chloride to a cooled solution comprising about 1.0 g tyramine and about 2.03 ml of triethylamine in 35 ml of tetrahydrofuranol (THF). The reaction mixture was stirred at room temperature for 48 hours. It was then poured into about 70 ml of 10% HCl solution and the mixture extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (MgSO4) and concentrated under reduced pressure to give a crude N-nonanoyl tyramine product. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][S:14][CH3:15])[CH:7]=1)[C:3]([OH:5])=[O:4].I([O-])(=O)(=O)=[O:17].[Na+]>>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][S:14]([CH3:15])=[O:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: CSCc1cc(C(N)C(=O)O)ccc1O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Product: CS(=O)Cc1cc(C(N)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an aqueous solution (500 ml) of α-amino-4-hydroxy-3-[(methylthio)methyl]benzeneacetic acid (1 mole) is added sodium metaperiodate (1 mole). The mixture is stirred at room temperature for 5 hours, it is filtered and the filtrate is lyophilized to give a quantitative yield of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11](=O)[CH3:12].[CH3:14][NH:15][NH2:16].ClC(Cl)C(Cl)Cl>C(O)C.[O-2].[Mn+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:15]([CH3:14])[N:16]=[C:11]([CH3:12])[CH:10]=1
Reactant: CNN
Reactant: CC(=O)C=Cc1c(F)cccc1F
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCO
Solvent: ClC(Cl)C(Cl)Cl
Product: Cc1cc(-c2c(F)cccc2F)n(C)n1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a mixture of 4-(2,6-difluorophenyl)-3-buten-2-one (i.e. the product of Step A) (8.1 g, 44.5 mmol) in ethanol (50 mL) was added methylhydrazine (2.1 g, 49 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure. To the resulting oil (10.1 g) was added 1,1,2,2-tetrachloroethane (65 mL) and manganese oxide (41.7 g, 480 mmol). The reaction mixture was heated at 140° C. for 20 minutes, and then cooled to room temperature and filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel rinsing with dichloromethane (2×20 mL). The filtrate was concentrated under reduced pressure and the resulting material was purified by MPLC (10 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a light yellow solid (4.02 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([CH2:23][C@H:24]([NH:32][C:33](=[O:53])[C@@H:34]([NH:41][C:42](=[O:52])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[NH2:44])[CH2:35][C:36]2[N:37]=[CH:38][NH:39][CH:40]=2)[C@@H:25]([OH:31])[C@H:26]([CH:28]2[CH2:30][CH2:29]2)[OH:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:23][C@H:24]([NH:32][C:33]([C@@H:34]([NH:41][C:42]([C@@H:43]([NH:44][C:14]([C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:13])=[O:16])[CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:52])[CH2:35][C:36]2[N:37]=[CH:38][NH:39][CH:40]=2)=[O:53])[C@@H:25]([OH:31])[C@H:26]([CH:28]2[CH2:29][CH2:30]2)[OH:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 21, by replacing Boc-D-proline by N-benzyloxycarbonyl-D-alanine in the condensation with (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide there was obtained benzyl [(R)-1-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]ethyl]carbamate as an amorphous solid, MS: 717 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].CC[O:17]CC.Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([OH:17])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOCC
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 3-bromo-2,4-difluoro-1-nitrobenzene (10.5 g, 44 mmol) in dimethyl sulfoxide (85 ml) was stirred at ambient temperature. A solution of potassium hydroxide (14.1 g, 251 mmol) in water (21 ml) was added dropwise over 15 minutes. The black reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then poured onto water (200 ml) and three ether extractions (100 ml) were performed. The aqueous layer was acidified with concentrated hydrochloric acid and extracted three times with ether (100 ml). The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give a yellow solid (9.7 g, 93% yield). Recrystallization from isopropyl ether afforded an analytical sample: m.p. 65°-66° C. NMR (CDCl3, 60 MHz): 8.1 (dd, 1H, J=10, 5 Hz), 6.8 (dd, 1H, J=10, 8 Hz)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([P:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[S:32]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)([O:35][CH3:36])(=[O:34])=[O:33]>>[S:32]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)([O-:35])(=[O:34])=[O:33].[CH3:36][P+:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: FC(F)(F)c1cccc(P(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)c1
Product: C[P+](c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 88 %

Procedure:
A mixture of 6.20 g (13.3 mmol) of tris(3-trifluoromethylphenyl)phosphine and 2.94 g (15.8 mmol) of methyl tosylate were allowed to react for 3 hr at 140° C. A total of 7.64 g (11.7 mmol, 88.0 %) of product was obtained, which was further purified by recrystallization from toluene-ethanol.
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]([CH3:30])([O:7][C:8]([NH:10][C@H:11]([C:22]([NH:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])=[O:23])[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21])=[O:9])[CH3:6].CN1CCOCC1.[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCOC(C)=O>[CH3:4][C:5]([CH3:6])([O:7][C:8]([NH:10][C@H:11]([C:22]([NH:24][C@@H:25]([C:27]([NH:47][CH2:46][CH2:45][CH2:44][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:29])[CH3:26])=[O:23])[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21])=[O:9])[CH3:30]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)O
Reactant: NCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Temperature: -45 °C
Reaction time: 8 h

Procedure:
A CH2Cl2 solution (100 ml) of the title compound from Example 9, (16.6 g, 43.6 mmole) was charged with 4.4 g (43.6 mmoles) of NMM and cooled to -45° C. To this solution was added 5.7 g (43.6 mmole) of IBCF and the mixture warmed to 10° C. The solution was then cooled to -25° C. before adding 7.4 g (54.5 mmole) of 3-phenylpropylamine. After allowing the reaction to warm to room temperature and stand overnight, it was diluted with 300 ml of EtOAc and extracted with three 100 ml portions of 0.5N KHSO4. The combined aqueous washes were extracted with 100 ml of EtOAc and this extract was combined with the original organic phase. The combined organic was then washed with one 150 ml portion of brine before drying it over Na2SO4. All solvent was removed under reduced pressure to give the title product as a foam. This material was chromatographed to give 10 g (46%) of a compound identical to diastereomer S of Example 3.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH2:12]([N:15]1[C:24](=[O:25])[CH:23]=[C:18]2[S:19][CH2:20][CH2:21][CH2:22][N:17]2[C:16]1=[O:26])[CH2:13][CH3:14].CN([CH:30]=[O:31])C>>[CH:30]([C:23]1[C:24](=[O:25])[N:15]([CH2:12][CH2:13][CH3:14])[C:16](=[O:26])[N:17]2[CH2:22][CH2:21][CH2:20][S:19][C:18]=12)=[O:31]
Reactant: CN(C)C=O
Reactant: CCCn1c(=O)cc2n(c1=O)CCCS2
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(=O)c(C=O)c2n(c1=O)CCCS2
Yield: 95 %

Procedure:
The Vilsmeier reagent prepared from phosphorus oxychloride (3.7 ml) and DMF (6.2 ml) was added dropwise to a solution of 7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (6 g) in DMF (38 ml) with stirring under ice cooling. The reaction solution was stirred at room temperature for 3 hours and then, poured on ice water. The mixture was stirred for a while and the precipitated crystals were recrystallized from ethyl acetate to give colorless crystals (6.46 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1.[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:21][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCN
Reactant: Fc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1F
Product: CCNc1nc(Cl)nc2c1COCC2c1ccc(F)c(F)c1

Procedure:
2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Y) was reacted as described in Preparation Xa with ethanamine to give 2-chloro-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Ya). LC-MS (M+H)+=326.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][N:39]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCN(S(C)(=O)=O)CC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
In a 10 mL round-bottomed flask, 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one (35.03 mg, 57.5 μmol, Eq: 1.00) was combined with DCM (3 ml) and cooled to 0° C. DIPEA (8.91 mg, 12.0 μl, 68.9 μmol, Eq: 1.2) was added, followed by addition of methanesulfonyl chloride (6.58 mg, 4.48 μl, 57.5 μmol, Eq: 1). The reaction mixture was stirred at 0° C. to room temperature for 1 hr. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 5% of MeOH in 50% EtOAc/Hexane) to afford white solid (16 mg, 45%). (M+H)+=688.4 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.56 (s, 1H), 8.48 (br. s., 1H), 8.29 (br. s., 1H), 8.20 (br. s., 1H), 7.42-7.70 (m, 6H), 7.04 (d, J=8.2 Hz, 1H), 4.42 (br. s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.95 (d, J=11.3 Hz, 2H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.62 (t, J=11.5 Hz, 1H), 2.04 (s, 3H), 1.77-1.99 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH2:46][NH2:47]>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:47][CH2:46][C:45]4[CH:48]=[CH:49][CH:50]=[C:43]([O:42][CH3:41])[CH:44]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: COc1cccc(CN)c1
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)c1
Yield: 59.4 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (0.538 g, 1.0 mmol) and dimethyl sulfoxide (0.35 mL, 4.9 mmol, 5 eq.) in acetonitrile (6 mL) was added 3-methoxybenzylamine (0.26 mL, 2.0 mmol, 2 eq.) and the reaction mixture was heated to reflux for 45 hours. The cooled reaction mixture was then concentrated in vacuo to remove acetonitrile. The oily residue was dissolved in ethyl acetate (25 mL), washed with 1N sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product (0.59 g) as a brown foam. Purification by flash chromatography using a solvent gradient of 20 to 40% ethyl acetate in hexane gave the title compound (330 mg, 59%) as a pale yellow solid. MS [(+)ESI, m/z]: 556 (M+H]+.HRMS [(+)ESI, m/z]: 556.25884 [M+H]+. Calcd for C36H34N3O3: 556.26002. Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N 7.56. Found: C, 77.50; H, 6.10; N 7.43.