Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:11][C:10]1[C:9]2[C:12]([CH2:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1oc2cccc(CC)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.8 %

Procedure:
To a solution of 0.380 g (1.64 mmol) of 3-methyl-4-ethylbenzofuran-2-carboxylicacid ethyl ester in 8 mL of methanol and 8 mL of THF was added 8.2 mL of 1N sodium hydroxide solution and the reaction was stirred for 14 h at room temperature and then acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 0.321 g of 3-methyl-4-ethylbenzofuran-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21]C)[CH:15]=1)[CH:7]=[C:6]([C:23]([O:25]CC)=[O:24])[C:5]2=[O:28].Br>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=1)[CH:7]=[C:6]([C:23]([OH:25])=[O:24])[C:5]2=[O:28]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(C)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(O)c3)c12
Yield: 80.4 %

Procedure:
Ethyl 6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.3 g) was added to a mixed liquid (1:1, v/v; :30 ml) of 47% hydrobromic acid and acetic acid, and the mixture was stirred and refluxed for 44 hours. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (1.65 g) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH2Cl2 (25 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol), triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and then partitioned between Et2O and water. The water layer was extracted with Et2O. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to yield [1-(methoxy-methyl-carbamoyl)-cyclopropyl]carbamic acid tert-butyl ester which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1Cl)(=[O:9])=[O:8].[H-].[Na+].[OH2:23]>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[OH:23])(=[O:9])=[O:8]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 68.6 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(3-methylthiopropyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.0 g, 2.78 mmol), 60% NaH (330 mg, 8.13 mmol) and water (59 μL, 3.25 mmol) were reacted to form the desired product (650 mg, 69%). EI-MS (m/z) 339.86, 341.84 (M−).
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[C:28]([NH2:31])(=[S:30])[CH3:29].C(OCC)(=O)C>CO.ClCCl>[CH3:14][S:11]([O:10][C@H:8]1[CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:5]([C:3]2[N:31]=[C:28]([CH3:29])[S:30][CH:2]=2)[CH2:9]1)(=[O:12])=[O:13]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.15 g) in a mixture of methanol (20 ml) and dichloromethane (15 ml) was added thioacetamide (388 mg) at room temperature. After stirring at the same temperature for 4 hours, the mixture was poured into ethyl acetate and washed in turn with saturated aqueous sodium bicarbonate and brine. The dried organic layer was evaporated and the resulting oil was subjected to a column chromatography on silica gel (50 g) eluting with a mixture of acetone and dichloromethane (1:20 V/V) to give (2S,4R)-4-methanesulfonyloxy-2-(2-methylthiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (810 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1C(F)(F)F
Yield: 54.9 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (116 mg, 55%). MS (ISP) 423.3 [(M+H)+]; mp 177° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][O:7][C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].Cl[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32].O>C(#N)C>[CH2:34]([O:33][C:31]([N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][O:7][C:6]1=[O:9])[S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[O:32])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)COC(=O)Cl
Reactant: CC1CCN(Cc2ccccc2NS(=O)(=O)C(F)(F)F)C(=O)OC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N(c1ccccc1CN1CCC(C)COC1=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 52.3 %

Procedure:
6-Methyl-3-[2-(trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazepan-2-one (0.15 g, 0.41 mmol) and sodium hydrogen carbonate (0.06 g, 0.71 mmol) were suspended in acetonitrile (10 ml), added with isobutyl chloroformate (00.10 g, 0.73 mmol) and heated to reflux for three hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 3-(2-[N-(isobutoxycarbonyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-6-methyl-[1,3]-oxazepan-2-one (0.10 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=[C:44]([O:52][C@@H:53]2[CH2:57][C@@H:56]([C:58]([O:60][CH3:61])=[O:59])[NH:55][CH2:54]2)[C:43]=1[C:62]#[C:63][CH2:64][CH2:65][CH2:66][C@@H:67]1[CH2:69][C@H:68]1[O:70][C:71]([NH:73][C@@H:74]([C:78]1([CH3:84])[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1)[C:75](O)=[O:76])=[O:72])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][C:42]1[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N:45]=[C:44]2[O:52][C@H:53]3[CH2:54][N:55]([C:75](=[O:76])[C@H:74]([C:78]4([CH3:84])[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83]4)[NH:73][C:71](=[O:72])[O:70][C@@H:68]4[CH2:69][C@H:67]4[CH2:66][CH2:65][CH2:64][C:63]#[C:62][C:43]=12)[C@H:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:57]3)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c(OCc3ccccc3)c2C#CCCC[C@@H]2C[C@H]2OC(=O)N[C@H](C(=O)O)C2(C)CCCCC2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A round-bottom flask was charged with HATU (1711 mg, 4.50 mmol) and dry DMF (2.25E+04 μl) at 0° C. N,N-diisopropylethylamine (1531 μl, 9.00 mmol) was added followed by addition of a solution of the product of step 3 (1827 mg, 2.25 mmol) in dry DMF (2.25E+04 μl) via syringe pump over 1 hour. After addition was complete the reaction was stirred at room temperature for 2 hours. LCMS and MS analyses showed a complete reaction. The reaction mixture was concentrated to almost dryness in rotavap (high vacuum) and the residue was diluted with ethyl acetate (200 mL). The mixture was washed with water (50 mL), aq. 1M HCl (50 mL), half-saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a Redisep (120 g) silica gel column (gradient: 0 to 40% ethyl acetate in hexanes) to give the title compound (900 mg, 1.324 mmol, 58.8% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][C:23]([CH2:31][CH3:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:4][C:3]=1[N+:33]([O-])=O.CCOC(C)=O>[Pd]>[NH2:33][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][C:23]([CH2:31][CH3:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:2]=1[NH2:1]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(-c4ccccn4)c(N)c([N+](=O)[O-])c3)cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(N)c(N)c(-c4ccccn4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 1-(5-(4-amino-3-nitro-5-(pyridin-2-yl)phenyl)pyrimidin-2-yl)-4-ethylpiperidine-4-carboxylate (0.70 g, 1.46 mmol) in EtOAc (20.0 mmol) was added Pd/C (0.14 g, 20% w/w) and the mixture stirred at rt under hydrogen for 16 h. After completion the reaction (by TLC), the mixture was filtered through celite, the filtrate concentrated under reduced pressure and triturated with Et2O to afford the desired product (0.65 g, 99%). 1H NMR (DMSO-d6): δ 8.61-8.62 (m, 1H), 8.58 (s, 2H), 7.86-7.88 (m, 2H), 7.28-7.30 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.16 (s, 2H), 4.78 (br s, 2H), 4.38-4.42 (m, 2H), 4.13-4.18 (m, 2H), 3.04-3.10 (m, 2H), 2.04-2.08 (m, 2H), 1.55-1.57 (m, 2H), 1.37-1.39 (m, 2H), 1.19 (t, J=7.20 Hz, 3H) and 0.83 (t, J=7.20 Hz, 3H). MS: 447.35 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[OH-].[Na+].[O-:14]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].Cl>O.C(OCC)(=O)C>[OH:11][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([OH:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cc1cccc(C(=O)O)c1O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C(=O)O)c1O
Temperature: 25 °C
Yield: 71.7 %

Procedure:
The synthesis was performed with reference to the known literature (Canadian Journal of Chemistry, Vol. 50, p. 1276, 1972). 3-Methylsalicylic acid (6.0 g, 39 mmol) was added with 10% aqueous sodium hydroxide (80 mL), and the mixture was stirred at room temperature. The reaction mixture was added portionwise with a suspension of potassium peroxodisulfate (10.8 g, 40 mmol) in water (150 mL), and then the mixture was stirred at room temperature for 12 hours. The reaction mixture was made acidic with concentrated hydrochloric acid, and then extracted with diethyl ether to remove the unreacted starting material. Then, the aqueous layer was added with concentrated hydrochloric acid (40 mL), and the mixture was refluxed by heating for 2 hours. The reaction mixture was cooled to room temperature, and extracted with diethyl ether, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the solid formed was suspended in ethyl acetate, and then collected by filtration to obtain 2,5-dihydroxy-3-methylbenzoic acid (4.7 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[CH:5]=[N:6][CH:7]=1.[NH2:11][C@@:12]1([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:16][CH2:15][O:14][CH2:13]1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C@@:12]2([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:16][CH2:15][O:14][CH2:13]2)=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CCCCOC(=O)[C@]1(N)CCOC1
Reactant: Nc1cncc(C(=O)O)c1
Product: CCCCOC(=O)[C@]1(NC(=O)c2cncc(N)c2)CCOC1
Yield: 96 %

Procedure:
Analogously to Example 1c), 5-aminopyridine-3-carboxylic acid (72.4 mmol) was reacted with n-butyl(S)-3-amino-tetrahydrofuran-3-carboxylate (72.4 mmol). The product was obtained in a yield of 96% of theory.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][P:8]([CH:13](O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6].C(Cl)[Cl:24].N1C=CC=CC=1>O>[CH2:5]([O:7][P:8]([CH:13]([Cl:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: CCOP(=O)(OCC)C(O)c1ccc(OC)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)C(Cl)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
9.2 g (0.0768 mol) of thionyl chloride were added to a mixture of 20.2 g (0.0725 mol) of 4-methoxy-α-hydroxy-benzyl-phosphonic acid diethyl ester, 65 g of methylene chloride and 5.8 g (0.0725 mol) of pyridine at 20°-40° C. in the course of about 1 hour, while cooling slightly with water. The reaction mixture was then heated under reflux for 3 hours and subsequently stirred for 12 hours, without further action of heat. The mixture was poured into about 100 g of ice-water and the organic phase was separated off and dried. After distilling off the solvent, the residue was concentrated under 6 mm Hg and at 45° C. 21 g (97.7% of theory) of 4-methoxy-α-chloro-benzyl-phosphonic acid diethyl ester were obtained as a yellow viscous oil with a purity of 98.6% (gas chromatogram) and with a refractive index of nD24 : 1.5118.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([P:6]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[OH:30]O.[PH3]=O>C(#N)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([P:6](=[O:30])([C:4](=[O:5])[C:3]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:2]=1[Cl:1])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:24]
Reactant: Cc1ccc(C)c(P(C(=O)c2c(Cl)cccc2Cl)C(=O)c2c(Cl)cccc2Cl)c1
Reactant: OO
Agent: O=[PH3]
Solvent: CC#N
Product: Cc1ccc(C)c(P(=O)(C(=O)c2c(Cl)cccc2Cl)C(=O)c2c(Cl)cccc2Cl)c1
Temperature: 60 °C
Yield: 74 %

Procedure:
The crude bis-(2,6-dichlorobenzoyl)-2,5-dimethylphenylphosphine (50 grams) is dissolved in 1 liter acetonitrile, mixed with 150 ml of 30% hydrogen peroxide, and heated for one hour at 60° C. The formation of the phosphine oxide is accompanied by deepening of the color, and it precipitates in crystalline form, after the addition of water and cooling. Recrystallization from acetonitrile/water yields 37 grams of the captioned compound (74% of theoretical yield in 2 steps)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:31])[NH:23][C:24]2[S:25][C:26]([S:29][CH3:30])=[CH:27][N:28]=2)[CH:17]=1)(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:31])[NH:23][C:24]2[S:25][C:26]([S:29]([CH3:30])=[O:9])=[CH:27][N:28]=2)[CH:17]=1)(=[O:14])[CH3:13]
Reactant: CSc1cnc(NC(=O)c2cccc(OC(C)=O)c2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)Nc2ncc(S(C)=O)s2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.4 %

Procedure:
A solution of m-chloroperbenzoic acid (0.458 g, 2.04 mmol, maximum 77%) is dissolved in dichloromethane (8.0 mL) and added dropwise over 15 minutes to a solution of 516 (0.630 g, 2.04 mmol) dissolved in dichloromethane (25.0 mL). The reaction is stirred at room temperature for 6 hours. The reaction is then partitioned between dichloromethane and saturated aqueous sodium thiosulfate. The organic layer is washed again with a saturated aqueous sodium thiosulfate, twice with saturated aqueous sodium bicarbonate and once with brine. The dichloromethane layer is dried over magnesium sulfate and concentrated in vacuo to give crude 8 (0.704 g, >100%), which is contaminated with traces of residual 3-chlorobenzoic acid. The crude product is re-dissolved in ethyl acetate and washed three times with a saturated aq. sodium bicarbonate, dried using magnesium sulfate and concentrated in vacuo to give a tan solid. The residue is dissolved in THF, and the light brown solution was filtered through a plug of Magnesol. The filter pad is washed well with THF, and the colorless filtrate is concentrated in vacuo to give 8 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]3[CH:10]2[C:11](=[O:16])O[C:13]3=[O:15])=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:11](=[O:16])[CH:10]3[CH:14]([CH:9]3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]2=[O:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(C2C3C(=O)OC(=O)C32)cc1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C3C(C2=O)C3c2ccc(OC)cc2)cc1
Temperature: 180 °C
Yield: 63 %

Procedure:
A mixture of 6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (crude product from the previous step) and (4-methoxyphenyl)methanamine was heated at 180° C. for 1.5 h. After cooling to room temperature, the reaction mixture was dissolved in CH2Cl2 and purified by flash column chromatography with EtOAc in hexane (20%, 30%, then 40%) to give the title compound as a yellow solid (0.71 g, 63% yield over three steps). MS [M+H]+: 338.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:21][CH2:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][CH2:28]3)[C:7]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(=O)CO2

Procedure:
6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (310 mg, 1.73 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) (2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) afforded the product as a solid (58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[C:14]([Cl:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: O=C1CCC(=O)N1Cl
Product: CCOCc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-ethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:38])[N:36](O)[C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].P(OCC)(OCC)OCC>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:38])[NH:36][C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(n1O)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Agent: CCOP(OCC)OCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c([nH]1)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 100 °C
Yield: 37.4 %

Procedure:
To a solution of tert-butyl(1-(4-(3-hydroxy-2-methyl-8-phenyl-4,5-dihydro-3H-imidazo[4,5-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (276 mg, 0.528 mmol) in anhydrous DMF (1.4 mL) was added triethyl phosphite (181 μl, 1.056 mmol) and heated to 100° C. under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with 50:50 water:brine (10 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were washed with 50:50 water:brine (2×10 mL), brine (10 mL) dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified via Biotage chromatography (silica, DCM:MeOH, gradient elution from 100:0 to 90:10) to give the desired product as a pale brown solid (100 mg, 37% yield). 1H-NMR (500 MHz, CDCl3) δ 7.74 (1H, s), 7.28 (2H, d), 7.23 (2H, d), 7.13-7.17 (3H, m), 7.06-7.11 (2H, m), 5.09 (1H, br s), 3.25 (2H, t), 2.92 (2H, t), 2.16-2.59 (4H, br m), 2.41 (3H, s), 1.95-2.08 (1H, m), 1.70-1.82 (1H, m), 1.05-1.47 (9H, br m). LCMS (Method A) RT=4.66 min, M+H+=507.20.