Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[C@@H:24]1[CH2:28][CH2:27][O:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O[C@@H]1CCOC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6 ml acetonitrile are combined with 114 μl (R)-3-hydroxy-tetrahydrofuran and 370 mg triphenylphosphine. Then 234 μl diethyl azodicarboxylate are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is filtered and the filtrate evaporated down in vacuo. The crude product is purified by chromatography over a silica gel column with ethyl acetate/-methanol (95:5) as eluant.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]([NH:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]1[O:25][C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc([N+](=O)[O-])cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.9 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-nitrobenzohydrazide (8.5 g, 15.57 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (8.17 g, 31.13 mmol), iodine (7.90 g, 31.13 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 50 minutes and quenched with sat. aq. sodium thiosulfate (400 mL). The solution was extracted with CH2Cl2 (250 mL). The organic extract was washed with sat. aq. sodium thiosulfate (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a light yellow solid (5.5 g, 67%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 5.11 (d, J=9.2 Hz, 1H), 4.87 (dd, J=3.9, 8.8 Hz, 1H), 4.46 (dq, J=3.7, 6.3 Hz, 1H), 2.34 (s, 3H), 1.31 (d, J=6.3 Hz, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCn1c(SC)nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Solvent: COCCOC
Product: CCn1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 71.3 %

Procedure:
In a mixture of DME (15 ml) and ethanol (1.5 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (221 mg) followed by addition of acetic acid (185 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound could be verified by TLC. The catalyst was then filtered off and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in the order mentioned, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (141 mg).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11](=O)[CH2:12][CH3:13])#[N:2].[OH:15]O.O.[OH-].[Na+]>C(O)C.C(O)(=O)C>[CH2:12]([C:11]1[N:2]=[C:1]([OH:15])[C:3]2[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=2[N:10]=1)[CH3:13]
Reactant: OO
Reactant: CCC(=O)Nc1c(C)nn(C)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1nc(O)c2c(n1)c(C)nn2C
Temperature: 80 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
The above propionamide (18 g, 0.094 mol) is added in portions to a solution prepared by adding 24 ml of 30% hydrogen peroxide to 250 ml of water containing 6 g (0.15 mol) of sodium hydroxide. The mixture is stirred at 80° C. for five hours, cooled and acidified with acetic acid to give 12.7 g (70%) of 5-ethyl-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol, mp 220°-222° C. from ethanol.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.CCN(C(C)C)C(C)C.O[CH2:32][C:33]1[CH:34]=[C:35]([CH:63]=[CH:64][CH:65]=1)[O:36][C:37]([O:39][CH2:40]/[C:41](/[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)=[C:42](/[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)\[C:43]([O:45][CH3:46])=[O:44])=[O:38]>C(Cl)Cl>[Br:20][CH2:32][C:33]1[CH:34]=[C:35]([CH:63]=[CH:64][CH:65]=1)[O:36][C:37]([O:39][CH2:40]/[C:41](/[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)=[C:42](/[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)\[C:43]([O:45][CH3:46])=[O:44])=[O:38]
Reactant: BrBr
Reactant: COC(=O)/C(=C(\COC(=O)Oc1cccc(CO)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C(=C(\COC(=O)Oc1cccc(CBr)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 470 mg of Ph3P in 15 mL of CH2Cl2 cooled at 0° C. was added 1.75 mL of a 1.0M Br2 solution in CH2Cl2. After 10 min, 340 μL of Hunig's base was added followed by 798 mg of methyl (2Z)-4-({[3-(hydroxymethyl)phenoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoate dissolved in 20 mL of CH2Cl2. After 15 min at 0° C., the reaction mixture was warmed to rt for 1 h. The reaction was quenched with H2O, extracted twice with EtOAc and washed with brine, dried over sodium sulfate, evaporated, and purified by flash chromatography (10–50% EtOAc/hexane) to afford 786 mg of the title compound as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25](I)[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.[Cu]I.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>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([C:42]#[C:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(C#Cc4ccccc4)ncn3)[C@@H]2O1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of N-[(3a S,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-iodopyrimidin-4-amine (0.300 g, 0.594 mmol) in DMF (2.46 mL) was added CuI (0.0113 g, 0.0594 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.0292 g, 0.0415 mmol). The tube was sealed and flushed with argon. Et3N (0.165 mL, 1.19 mol) was added and the reaction was stirred for 1 h. Phenylacetylene (0.216 mL, 1.96 mmol) was added and the reaction was stirred overnight. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography (10 to 40% EtOAc/hexanes) to afford the title compound as a yellow oil (0.238 g, 84%). LC/MS: Rt=2.47 min, ES+ 480 (FA standard).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5](CC2C=CC(OC)=CC=2)[C:4](=[O:25])[C:3]=1[C:26]#[N:27].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:25])[C:3]=1[C:26]#[N:27]
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(OC)c(OC)cc32)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc2[nH]c(=O)c(C#N)c(Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-1-(4-methoxybenzyl)2-oxo-1,2-dihydroquinoline-3-carbonitrile (300 mg), trifluoroacetic acid (5 ml), anisole (2 ml) and trifluoromethanesulfonic acid (1 ml) was stirred at room temperature for 1 day. After concentoration, the residue was cooled to 0° C. and ethyl acetate was added. The pH was adjusted to about 9 by adding 5% sodium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The concentrated residue was purified with silica gel column chromatography to obtain the target compound (125 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1(C(O)=O)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC#N>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([NH2:39])([CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[CH3:1])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccccc1CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To a mixture of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid (1.0 g, 3.0 mmol) in CH3CN (20 ml) add diphenyl phosphoryl azide (0.99 g, 3.6 mmol) and triethylamine (0.50 ml, 3.6 mmol). After stirring at 55° C. (oil bath temp.) concentrate the reaction in vacuo and partion the residue between EtOAc and saturated aqueous NaHCO3. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo to afford the crude product.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CCOC(C)=O.Cl>[CH3:15][C:2]1([CH3:16])[O:1][C:32](=[O:33])[C:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:3]1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)C(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold solution (0° C.) of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-propane-1-one (726 mg, 3.5 mmol, Step 3), pyridine (0.5 mL, 6.2 mmol) in CH2Cl2 (10 mL) was added 4-methoxyphenylacetyl chloride (1.5 g, 8.4 mmol) over 2 minutes. The resulting yellow solution was stirred at r.t. for 18 h. Then DBU was added in portions every 30 min. (3×1.0 mL, 3×6.7 mmol). The reaction was diluted with EtOAc (100 mL) and 1N HCl (50 mL). The organic layer was washed with water (50 mL), dried over MgSO4 and concentrated. The crude product was purified first by flash chromatography eluted with 40% EtOAc in hexane and then by crystallization in EtOAc and hexane (1:1, 26 mL) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8](O)=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].S(=O)(=O)(O)O.P(=O)(O)(O)O.[H][H].[OH-].[Na+]>O.[Pt].[Re].[Ru].[Pt].[Ru].[Re]>[NH2:1][C@H:2]([CH2:8][OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: [H][H]
Agent: [Pt]
Agent: [Re]
Agent: [Ru]
Solvent: O
Product: NCCCC[C@H](N)CO
Temperature: 25 °C

Procedure:
In particular, the process comprises charging a high pressure reactor with a solution of lysine in water, acid, and a hydrogenation catalyst. The high pressure reactor may be a batch, continuous, or semi-continuous reactor. The acid including, but not limited to sulfuric acid or phosphoric acid, is present in an amount of at least 0.5 molar equivalent of lysine or 1 molar equivalentor of lysine or 2 molar equivalent of lysine. Alternatively, the pH of the aqueous lysine solution can be adjusted with an acid to a pH in the range of 1-5 or 1.5-4 or 2-3. The catalyst is present in an amount in the range of 0.2-50% or 0.5-10% or 1-5% by weight of the total reaction mass. The hydrogenation catalyst can be chosen from those known in the art, for example ruthenium supported on carbon, platinum supported on carbon, platinum supported on titanium dioxide, or supported rhenium-ruthenium or rhenium-platinum catalysts. The process further comprises filling the reactor with hydrogen up to a pressure in the range of 0.7-14 MPa or 1.5-11 MPa or 2-9 MPa at a temperature in the range of 50-220° C. or 100-200° C. or 120-180° C. The process also comprises maintaining the pressure until ceasing of hydrogen uptake. The process further comprises cooling the reactor to room temperature and adding sodium hydroxide until pH is greater than 12. The process also comprises removing water and extracting the resulting residue, a mixture of lysinol and salt, with a solvent that will dissolve lysinol but not the salts and then removing the solvent to obtain lysinol in the form of a colorless oil. In an embodiment, the lysinol is enantioenriched (S)-lysinol. In another embodiment, the ratio of (S)-lysinol to (R)-lysinol is in the range of 99.9:0.1 to 51:49 or 98:2 to 70:30 or 95:5 to 80:20.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=3)[CH2:7][CH2:6]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
To a mixture of 13.5 g. (50 mmole) ethyl 4-(piperazin-1-yl)-benzoate hydrochloride and 130 ml. anhydrous pyridine are added, at 5°-10° C., 50 mmole 4-chlorobenzoyl chloride. The temperature is allowed to come to 20° C. and the reaction mixture is subsequently stirred for 6 hours at 40° C. After cooling, it is stirred into 400 ml. ice water, extracted twice with 250 ml. amounts of methylene chloride and the organic phase is dried with anhydrous sodium sulphate and evaporated in a vacuum. The residue is triturated with ligroin and recrystallised from 150 ml. ethanol to give 15.6 g. of the desired product as colourless crystals; m.p. 147°-150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7].C(=O)([O-])[O-].[K+].[K+].C([O:37][C:38](=[O:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41])C.CN(C1C=CC=CN=1)C.O.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][CH2:5][C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:10][C@H:9]2[CH3:23])=[O:7])=[C:2]([NH:1][S:40]([CH2:39][C:38]([OH:44])=[O:37])(=[O:42])=[O:41])[CH:27]=1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1N
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CC(=O)O

Procedure:
To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.030 g, 0.074 mmol) in dimethylformamide (0.5 ml) was added potassium carbonate (0.030 g, 0.239 mmol), chlorosulfonyl-acetic acid ethyl ester (0.02 g, 0.12 mmol) (for preparation, see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) in dimethylformamide (0.5 ml) and finally catalytic dimethylaminopyridine. After 23 hours the reaction was diluted with ethyl acetate and washed with pH 7.0 phosphate buffer (0.05 M). The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude ester was then dissolved in 1:1 tetrahydrofuran:water (0.5 ml) and lithium hydroxide hydrate (0.004 g, 0.095 mmol) was added. After 19 hours the reaction was concentrated and the title compound purified by silica gel chromatography (0.006 g, LRMS: 528.3).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:13]C)[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:7][CH3:8].[Cl-].[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](O)=[O:23])[CH:20]=1.Cl>ClCCl>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](=[O:23])[C:10]2[CH:11]=[CH:12][C:5]([OH:13])=[C:6]([O:7][CH3:8])[CH:9]=2)[CH:20]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)c2ccc(O)c(OC)c2)c1

Procedure:
14.8g of aluminum chloride and 5g of veratrole are added to a solution of 7.34g of isophthalic acid monomethyl ester chloride in 160 ml of dichloromethane under ice cooling. The reaction mixture is refluxed for 8 hours, poured on ice water, acidified with 2 n of hydrochloric acid and shaken out with dichloromethane. The organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate=8/2. 3.5g of 3-(4-hydroxy-3-methoxybenzoyl)-benzoic acid methyl ester of melting point of 133°-134° C. is obtained.
Reaction SMILES: [I-].[CH3:2][CH:3]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].CC(C)([O-])C.[K+].[Br:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[C:3]([CH3:4])[CH3:2])=[CH:35][N:36]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)=Cc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of (1-methylethyl)(triphenyl)phosphonium iodide (72.2 g) in N,N-dimethylformamide (200 mL) was added a solution of potassium tert-butoxide (20.1 g) in N,N-dimethylformamide (100 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the reaction solution was added dropwise at 0° C. a solution of 6-bromopyridine-3-carbaldehyde (20.8 g) in N,N-dimethylformamide (200 mL). The reaction solution was warmed to room temperature, and the mixture was stirred at room temperature for 16 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:99-40:60, volume ratio) to give the title compound (16.2, yield 68%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].CC(=CC)C.[O-:30]Cl=O.[Na+].O>ClCCl.C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[C:23]([OH:30])=[O:24]
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C(=O)O)C3=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a mixture of 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (500 mg, 1.46 mmol), tert-butyl alcohol (20 mL), and dichloromethane (5 mL) was added 2-methyl-2-butene (3066 mg, 43.8 mmol). An aqueous solution (8 mL) of NaClO2 (263 mg, 2.92 mmol) and NaH2PO4.2 water (683 mg, 4.38 mmol) was added dropwise at −10° C. and the reaction mixture was stirred at −10° C. for overnight. It was concentrated under reduced pressure and the residue was extracted with ethyl acetate (4×20 mL). The combined organic extract was dried over MgSO4 and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 210a (315 mg, 60%) as a pale yellow solid. MS-ESI: [M+H]+ 360.1
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=[S:21])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.O.[Cl-].[NH4+]>CCO.CCOC(C)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=[S:21])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Temperature: 25 °C

Procedure:
A solution of 3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazine]-3′(4′H)-thione from Step E (628 mg, 2.0 mmol) in EtOH (16 mL) and EtOAc (8 mL) is treated successively with water (8 mL), iron powder (558 mg, 10 mmol) and ammonium chloride (53.5 mg, 1.0 mmol). The mixture is heated at reflux for 3 h and is then cooled to rt and filtered, washing the solids with additional EtOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacua, The residue is purified by silica gel chromatography (gradient elution with 0-10% MeOH in CH2Cl2) to afford the title compound.