Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27](=[O:30])[CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:26]([C:27](=[O:30])[CH2:28][CH3:29])[C@H:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH:5]=[CH:4][C:3]([OH:38])=[O:2])[CH:7]=3)[N:12]([C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([CH3:25])[CH2:10]2)=[CH:32][CH:33]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of (±)-cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid methyl ester (110 mg, 0.21 mmol) in 4 ml methanol was added 50 mg K2CO3, (0.36 mmol, in 2 ml water). The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed under vacuum. 1M HCl was added until the mixture was acidic. Dichloromethane (25 ml) was added. Organic layer was dried with magnesium sulfate. Dichloromethane was removed under vacuum. The residue was purified by HPLC to give 10 mg title compound
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:12]=3[N:3]12.[CH2:26]([C@H:33]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:26]([C@H:33]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:36]=[C:35]([C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:4]4=[N:5][NH:6][C:7](=[O:8])[C@@H:2]([CH3:1])[N:3]4[C:12]=3[CH:13]=2)[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of (R)-1-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (0.515 g, 1.5 mmol), (R)-tert-butyl 6-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.900 g, 2.13 mmol), Pd(dppf)Cl2—CH2Cl2 complex (0.309 g, 0.375 mmol) and K2CO3 (0.622 g, 4.50 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was heated at 90° C. for 4 h. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give (R)-tert-butyl 6-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.330 g, 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[F:23][C:24]1[N:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(F)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (125 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(6-fluoropyridin-3-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.5 (s, 1H), 8.21 (dd, 1H), 7.72 (m, 2H), 7.62 (s, 1H), 7.5 (d, 1H), 7.3 (s, 1H), 7.17 (m, 2H), 7.06 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.18 (s, 3H), 3.1 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@:5]([CH3:39])([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:50][C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:16]=2)[CH2:4][O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Yield: 70 %

Procedure:
A solution of (S)-tert-butyl 2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate (D8) (228 mg, 0.39 mmol) in toluene (5 mL) was treated with Lawesson's reagent (321 mg, 0.79 mmol). The reaction was chromatographed on a silica gel column eluted with ethyl acetate-hexane to afford the title compound (˜156 mg). MS (ESI): 572.17 (MH+), 1H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H, J=8.8 Hz), 8.08 (d, 1H, J=6.8 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.41 (d, 1H, J=8.0 Hz), 4.18 (d, 1H, J=9.6 Hz), 4.13-4.07 (m, 3H), 2.00 (s, 3H), 1.85 (m, 2H), 1.78 (s, 3H), 1.68 (m, 4H), 1.51 (s, 3H), 1.47 (m, 2H), 1.39-1.28 (m, 13H), 0.89 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[K].O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(NC1C=CC=CC=1)=O>C1(C)C(C)=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:5][CH:6]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Yield: 92 %

Procedure:
The highest yields at minimum reaction temperature are attained from essentially anhydrous potassium formanilide, but small amounts of water have little effect. From a reaction mixture of 31.8 parts by weight (0.2 mole) of dry potassium formanilide, 24.2 parts by weight (0.154 mole) of para-nitrochlorobenzene, 9.3 parts by weight (0.077 mole) of formanilide and 25 parts by weight of xylene there is obtained after heating at 137°-149° C. for about 125 minutes a 92% yield of 4-nitrodiphenylamine and 97% conversion. The addition of 0.5% weight and 1.0% by weight of water respectively based on the potassium formanilide results in little or no reduction in yield and conversion. Addition of 1.0% by weight 45% potassium hydroxide improves the yield slightly. The innocuous effect of a little free water is to be contrasted with the adverse effect of bound water. Potassium formanilide forms a monohydrate which hydrolyzes rapidly when heated above temperatures of 85°-90° C. Replacing about half the formanilide with aniline in the foregoing procedure gives comparable result. The presence of aniline reduces the by-product carbon monoxide about 40% with formation of formanilide by mechanism imperfectly understood.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: [N-]=[N+]=NC[C@H]1C=Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1C=Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
To a solution of ((R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-6-fluoro-2H-chromene (300 mg, 0.85 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.85 g, 2.6 mmol) and the reaction mixture stirred at room temperature for 43 hours. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under vacuum. Chromatography with 0–10% methanol in methylene chloride plus 1% NH4OH afforded {[(2R)-8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}amine as a colorless oil. The oil was dissolved in ethyl acetate and made into its hydrochlorde salt (83 mg, 27%) as a white crystalline solid using excess ethereal hydrochloric acid, mp 153–155° C.; [α]D25=+220.67° (c 1% solution in MeOH); MS (ES) m/z 324.0 ([M+H]+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>CN(C=O)C>[CH2:37]([N:38]([CH3:33])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH2:36][CH2:35][CH3:34]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Iodo-5-(methoxycarbonyl)benzoic acid (1 g, 3.3 mmol) is dissolved in DMF (10 mL), and diisopropylethylamine (1.7 mL, 9.8 mmol), HATU (1.5 g, 3.9 mmol), and N-methylbutylamine (581 μL, 4.9 mmol) are added. The reaction stirred at room temperature 2 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40% ethyl acetate/hexane) provides the title compound. ESI MS m/z 376.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]=[C:13]3[CH2:15][O:14]3)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:16][CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>O1CCOCC1.C(O)C>[CH:21]([N:19]1[CH2:20][CH:17]([NH:16][CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:10]2[C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[CH2:18]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc2cccc(OC=C3CO3)c2s1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc2cccc(OCC(O)CNC3CN(C(c4ccccc4)c4ccccc4)C3)c2s1

Procedure:
The title compound was prepared according to Method A from 2-methyl-7-(oxiranyl-2-ylmethoxy)benzothiazole and 3-amino-1-benzhydrylazetidine with dioxane/ethanol (1:1) as the solvent. mp 55° C.; LSIMS m/z 460. The 3-amino-1-benzhydrylazetidine was prepared as described in Preparation 96.
Reaction SMILES: [H-].C(N([Al](N(CCCCCC)CCCCCC)N(CCCCCC)CCCCCC)CCCCCC)CCCCC.[Li+].N[C@H](C(O)=[O:53])CC1CCCCC1.[C:55]([C:57]([C:60]1[CH:67]=[CH:66][C:63]([C:64]#N)=[CH:62][CH:61]=1)([CH3:59])[CH3:58])#[N:56]>C1COCC1>[CH:64]([C:63]1[CH:66]=[CH:67][C:60]([C:57]([CH3:59])([CH3:58])[C:55]#[N:56])=[CH:61][CH:62]=1)=[O:53]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CC(C)(C#N)c1ccc(C#N)cc1
Agent: CCCCCCN(CCCCCC)[Al](N(CCCCCC)CCCCCC)N(CCCCCC)CCCCCC
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(C=O)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
A suspension of lithium tris(dihexylamino)aluminum hydride, prepared according to Cha, J. S., et al; Org. Prep. Proc. Int. 1992, 24(3), 331-334, (21.2 g, 36 mmol) in THF (20 mL) was added via syringe to a solution of Example 35A (3.50 g, 20.6 mmol) in THF (50 mL) at 0° C. The reaction was allowed to proceed for 8 hr at 0° C., and then carefully quenched by addition of 3 N aq HCl(100 mL). The mixture was diluted with EtOAc, and the separated aqueous phase was extracted with EtOAc. The combined organic layer was washed with brine causing a white precipitate to form, which was filtered off. The filtrate was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting yellow solid was triturated with hexanes and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (Analogix® Intelliflash 280; 5% to 25% EtOAc/hexanes eluant; SF40-115 g column) to yield 2.24 g (63%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.00-7.93 (m, 2H), 7.80-7.74 (m, 2H), 1.73 (s, 6H). MS (DCI+) m/z 173 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C>[Pd].C1COCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[CH:2][CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2ccnc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50 mL round bottom flask fitted with a 3-way inlet was placed 10% Pd/C (0.071 g, 0.033 mmol) followed by degassing with N2, and then addition of 2 mL ethanol. Added next to the stirring slurry was 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.669 mmol). Additional ethanol (8 mL) and THF (10 mL) were added with slight warming to facilitate dissolution. The stirring contents were allowed to cool (15 min.) then fitted with a balloon of H2 and allowed to stir at room temperature overnight. The contents were then purged with N2. The mixture was then diluted with 10% MeOH/DCM (20 mL), stirred for 10 min., and filtered through Celite. The filtrate was concentrated in vacuo and the crude solid was triturated with ethanol. After filtration and washing the collected solid with additional ethanol (cold), the solid was air-dried for 15 min, then in vacuum oven at 40° C. overnight. The final product was collected as 185 mg (80%). LCMS E-S (M+H)=340.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.82 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.37 (d, J=4.80 Hz, 2H), 5.18-5.31 (m, 1H), 5.89 (s, 1H), 7.54 (d, J=4.80 Hz, 1H), 8.36 (s, 1H), 8.63 (d, J=4.55 Hz, 1H), 8.82 (t, J=4.93 Hz, 1H), 11.56 (s, 1H).
Reaction SMILES: [C:1]1([P:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:34]O>C(Cl)Cl>[C:28]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13]3)=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C1=CC(c2cccc3ccccc23)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Reactant: OO
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc2c1NC(c1cccc3ccccc13)C=C2
Yield: 90.7 %

Procedure:
Following the procedure described for the synthesis of compound 5,8-diphenylphosphino-2-naphthale-1-yl-1,2-dihydroquinoline (11) (8.8 g, 20 mmol) in CH2Cl2 (60 mL) was oxidised with H2O2 (4.15 mL, 30% w/w in H2O, 40 mmol) to give compound 12 (8.3 g) in 91% yield. 1H NMR (400.13 MHz, CDCl3) δ 8.00 (d, 1H, J=8.4 Hz, C5′—H), 7.83 (dd, 1H, J=7.6, 2.0 Hz, C8′—H), 7.7-7.6 (m, 3H, C2′—H/Ph-H), 7.6-7.5 (m, 3H, Ph-H), 7.5-7.4 (m, 5H, C6′/7′—H/Ph-H), 7.4-7.3 (m, 2H, Ph-H), 7.29 (d, 1H, J=8.0 Hz, C4′—H), 7.19 (t, 1H, J=8.0 Hz, C3′—H), 6.96 (d, 1H, J=7.2 Hz, C5—H), 6.64 (ddd, 1H, J=13.6, 7.6, 1.2 Hz, C7—H), 6.44 (td, 1H, J=7.2, 2.8 Hz, C6—H), 6.34 (dt, 1H, J=10.0, 1.6 Hz, C4—H), 6.32 (t, 1H, J=1.6 Hz, C2—H), 5.78 (dd, 1H, J=10.0, 4.0 Hz, C3—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.3, 148.2, 139.2, 132.9, 131.9 (d, J=11.1 Hz), 131.8 (d, J=12.1 Hz), 131.2 (d, J=10.1 Hz), 130.9 (d, J=9.1 Hz), 130.7, 129.8, 128.4, 127.8, 127.5 (d, J 12.1), 127.3 (d J 12.1), 126.6, 125.3, 124.7, 124.5, 123.8, 123.7, 123.4, 121.5, 121.5, 118.9, 114.2, 114.0, 108.9, 107.8, 52.6 ppm; 31P NMR (161.97 MHz, CDCl3) δ +35.2 ppm.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N)cc3)c12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1noc2cccc(Oc3ccc(N4C(=O)N[C@H](C)C4=O)cc3)c12
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
N1-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 14, 337 mg) was dissolved in 8.0 ml of ethyl acetate. Triethylamine (0.33 ml, 2.38 mmol) was added followed by a solution of triphosgene (161 mg, 0.54 mmol) in 2.0 ml of ethyl acetate. After 5 minutes stirring, DMAP (66 mg, 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated aqueous solution of NaHCO3, the reaction mixture was extracted two times with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient Cy-Hex/EtOAc from 100/0% to 0/100%. This afforded the title compound (160 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][Cl:22]>C(O)C>[ClH:22].[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([S:9][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ccccn1
Reactant: FC(F)(F)c1cccc(S)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1cccc(SCc2ccccn2)c1
Reaction time: 5 h
Yield: 56 %

Procedure:
m-Trifluoromethylbenzenethiol (5 g) was added to a solution of NaOH (2.25 g) in ethanol (50 ml) and the resulting solution was treated with a solution of 2-picolyl chloride, hydrochloride (4.6 g) in ethanol (25 ml) and the mixture was stirred for 5 hours. The resulting suspension was filtered through kieselghur and the solvent was removed by evaporation. The residue was converted into the hydrochloride in ether with ethereal HCl and recrystallised from acetone-ether to give 2-(((3-trifluoromethylphenyl)thio)methyl)pyridine hydrochloride (4.8 g) mp 145°-6° C. (Found: C,51.1; H,4.0; N,4.7 C13H10F3NS.HCl requires C,51.0; H,3.6; N,4.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>CS(C)=O.O>[CH2:28]([O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
1.5 gm (5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C., were stirred with 1.05 gm of potassium carbonate and 0.9 ml of n-butyl bromide in 15 ml of dimethyl sulfoxide for 60 hours. The mixture was subsequently diluted with water, and the reaction product was extracted with toluene. After washing, drying and evaporating the extract, the residue (1.7 gm) was recrystallized from cyclohexane. Yield: 1.2 gm (67% of theory); m.p.: 72°-74° C.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:29]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967) (1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])=[O:6])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(I)n2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a mixture of ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3.7 g, 6.41 mmol) in CH2Cl2 (80 mL) was added Dess-Martin Periodinane (2.72 g, 6.41 mmol) and the resulting mixture was stirred at rt for 1 hr. Then diluted with ethyl acetate (500 mL) and washed with sat. NaHCO3 solution (100 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired ethyl 6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2.5 g, 5.80 mmol, 91% yield) as off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.36 (s, 1H), 4.50 (dq, J=14.5, 7.1 Hz, 4H), 2.56 (s, 3H), 1.46 (t, J=7.2 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). LCMS (M+H)=431.87.