Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[Cl-].[Cl-].IC1C=CC=CC=1.[Na].[CH3:12][C:13]1([CH3:34])[S:17][C@@H:16]2[C@H:18]([NH:21][C:22]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C@H:14]1[C:31]([OH:33])=[O:32]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:12][C:13]1([CH3:34])[S:17](=[O:1])[C@@H:16]2[C@H:18]([NH:21][C:22]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C@H:14]1[C:31]([OH:33])=[O:32]
Reactant: O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Na]
Solvent: Ic1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1.5 h

Procedure:
5 ml of water and 3 g (10 mmoles) of iodobenzene dichloride in 40 ml of pyridine were added at -10° C with stirring to a suspension of 7.1 g (20 mmoles) of the sodium salt of benzylpenicillin in 160 ml of pyridine. The solution was stirred for 90 minutes and was poured into 200 ml of water and 500 ml of ethyl acetate. After adjusting the pH to 1.7 with HCl and extraction of the water layer several times with ethyl acetate, the combined organic layers were dried, concentrated and treated with diethyl ether and n-hexane. The obtained precipitate (3 g) was dissolved in water and sodium bicarbonate and the resulting solution was washed with methylene chloride, treated with decolorizing carbon, adjusted to a pH of 1.7 with HCl in the presence of methyl isobutylketone and extracted with methyl isobutylketone. The dried, concentrated organic layer was treated with diethyl ether and n-hexane and the precipitate was filtered off and dried to obtain 1.9 g of a mixture of benzylpenicillin, benzylpenicillin R-sulfoxide and benzylpenicillin-S-sulfoxide. 1.4 g of this precipitate was chromatographed on a column (65 cm in length, 2.5 cm in diameter filled with 180 g of silica gel and the eluent was a 97:3 (v/v) mixture of acetone and acetic acid. Fractions 30 to 71 contained 115 mg of the benzylpenicillin R-sulfoxide which was isolated by evaporating the solvent and dissolving the residue in ethyl acetate followed by precipitation with diethyl ether and n-hexane.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[N+:25]([O-])([OH:27])=[O:26]>O>[N+:25]([C:21]1[CH:20]=[CH:19][C:17]2[C:18]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:15](=[O:24])(=[O:23])[C:16]=2[CH:22]=1)([O-:27])=[O:26]
Reactant: O=S1(=O)c2ccccc2-c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 0 °C
Yield: 85 %

Procedure:
A 1 L three-neck round-bottom flask equipped with an addition funnel, mechanical stirrer, and thermocouple was charged with glacial acetic acid (110 mL) and sulfuric acid (110 mL) under nitrogen followed by dibenzothiophene-5,5-dioxide (50 g, 0.231 mol). The slurry was stirred and cooled to below 0° C. Fuming nitric acid, 90% (118 mL, 2.5 mol; specific gravity 1.5) was added dropwise over a period of 1.5 hours to keep the temperature below 4° C. The slurry was stirred for 30 minutes then poured onto 1.5 kg ice rinsing the flask with water. The product was collected by vacuum filtration, washed with water several times, and air dried followed by drying in a vacuum oven. The product was recrystallized from acetonitrile to give 51 g yellow crystals of 3-nitro-dibenzothiophene-5,5-dioxide (85% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[C-:32]#[N:33].[Na+].O>CN(C)C=O>[C:32]([C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:15])([F:16])[F:14])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])#[N:33]
Reactant: [C-]#N
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitro-benzamide (2.008 g, 4.4 mmol) (prepared according to WO 05/073165) in N,N-dimethylformamide (25 ml) was added sodium cyanide (0.237 g, 4.84 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. Then water (20 ml) was added and the organic phase extracted three times with ethyl acetate (3×100 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:4) to give 4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (1.0 g, 49% yield). 1H-NMR (400 MHz, CDCl3): 8.85 (d, 1H), 8.38 (q, 1H), 8.11 (d, 1H), 7.55 (s, 1H), 7.40 (s, 2H), 2.33 (s, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:40])[C:19]2[CH:24]=[N:23][C:22](S(C)(=O)=O)=[N:21][C:20]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:40])[C:19]2[CH:24]=[N:23][C:22]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:21][C:20]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COc1ccc(CCN)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCc3ccc(OC)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared 2-(4-methoxyphenyl)-ethylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1 Step E, 20 mg, 0.04 mmol). 19 mg of 8-Indan-5-yl-2-[2-(4-methoxy-phenyl)-ethylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.47 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.81 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 5.84 (br, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 3.34 (m, 2H), 3.00 (m, 7H), 2.64 (t, J=7.2 Hz, 2H), 2.18 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(=O)(=O)(O)O.[N+:12]([O-])([OH:14])=[O:13]>>[NH3:3].[CH3:1][C:2]1[NH:3][C:4]([N+:12]([O-:14])=[O:13])=[CH:5][N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: O=S(=O)(O)O
Product: Cc1ncc([N+](=O)[O-])[nH]1
Product: N
Reaction time: 1 h

Procedure:
Into a vessel made of acid-resistant stainless steel of 75 liters capacity, provided with a stirring device and a cooling jacket, a nitrated solution, obtained as in examples I or III, was placed and 6 kg of 2-methylimidazole were gradually introduced, while cooling and stirring, and then 20 liters of nitric acid of 1.40 density were introduced such that the temperature does not exceed 70°. The vessel was closed and connected by a valved conduit to an absorption device, provided with a cooled receiver. Sulphuric acid was gradually introduced until an increase of the temperature to 100° and the start of an intensive reaction was noted, this being associated with the eliminating of great quantities of nitric oxides. The addition of sulphuric acid was interrupted and the temperature maintained at 110°, by intensive cooling and periodic addition of condensates from the receiver, and to initially inhibit the reaction there is added in the first stage 1 liter of nitric acid of a density of 1.40. After stabilization of the reaction speed, a further uniform course of the reaction was maintained by gradual introduction of sulphuric acid to the use of a total amount of 20 liters, by simultaneously periodically filling up the nitrating vessel with the content of the receiver, when the reaction tended to become more violent. After the intensity of the reaction declined, which lasted about 1 hour, the cooling was interrupted and after five minutes the temperature gradually raised to about 140° and a fulfillment of the reaction at this temperature effected until the decline of the exothermic effect, at which time the solution was evaporated and condensed and the volatile components, which were liberated during this period, such as gases and vapors, have not been recycled to the reaction medium. After cooling of the reacted mixture, 1/4 of the volume of the solution was retained for treatment in the same way with the following charge and from the remaining quantity, after neutralization with ammonia, there were obtained 5.820 kg of 2-methyl-5-nitroimidazole corresponding to an output of about 64% of theoretical.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[F:10][C:11]([F:57])([F:56])[C:12]1[CH:13]=[C:14]([CH:53]=[CH:54][CH:55]=1)[CH2:15][NH:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:26]=2[NH:37][C:38]([C:40]2[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=2)[CH2:43][S:44][CH2:45][CH2:46][C:47](O)=[O:48])=[O:39])[CH:20]=1)=[O:18].O1CCN(CCNC(=O)CCSCC2C=C(C=CC=2)C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C=CN=2)C(NCC2C=CC=C(C(F)(F)F)C=2)=O)=O)CC1>ClCCl.C(O)(C(F)(F)F)=O>[N:31]1([C:29]2[CH:28]=[CH:27][C:26]([NH:37][C:38]([C:40]3[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=3)[CH2:43][S:44][CH2:45][CH2:46][C:47]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:48])=[O:39])=[C:25]([C:21]3[CH:20]=[C:19]([C:17](=[O:18])[NH:16][CH2:15][C:14]4[CH:53]=[CH:54][CH:55]=[C:12]([C:11]([F:57])([F:10])[F:56])[CH:13]=4)[CH:24]=[CH:23][N:22]=3)[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h

Procedure:
Tert-butyl glycinate was coupled to 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoic acid 1.1 using the procedure described for the synthesis of 2-(2-(3-(((3-((2-morpholinoethyl)amino)-3-oxopropyl)thio)methyl)benzamido)-5-(piperidin-1-yl)-phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 4.16. This material was dissolved in 2 mL of 1:1 dichloromethane/TFA and stirred for 1 h. The solvent was evaporated to give 4.6 mg of product. MS (ES, m/z): 734 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:33]=[CH:32][C:24]([C:25](/[N:27]=[CH:28]/[N:29](C)C)=O)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:38]N>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:33]=[CH:32][C:24]([C:25]3[NH:38][N:29]=[CH:28][N:27]=3)=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2)nc(-c2ccc(-c3ncn[nH]3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A mixture of the crude product of Step 1, 2 mL of acetic acid and 0.15 mL of anhydrous hydrazine was stirred at 90° C. for 30 min. The reaction mixture was diluted with MeOH and was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CD3OD): 8.08 (s, 1H), 8.05 (m, 4H), 7.73 (m, 2H), 7.58 (m, 3H), 7.35 (d, 2H), 7.11 (d, 2H), 3.68 (s, 3H), 1.61 (s, 6H). LCMS: m/z 421 (M+H)+.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([Mg]Br)[CH3:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:10]([C:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:11]
Reactant: O=C1CCCCCCC1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(O)CCCCCCC1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a 1000-mL 3-necked round bottom flask equipped with a 500-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 100 g (0.79 mol) of cyclooctanone dissolved in 250 mL of dry tetrahydrofuran. The addition funnel was charged with 290 mL (0.869 mol, 10% excess) of ethyl magnesium bromide (2.0M solution in ether) which was then added to the cooled ketone over 2 hours. Stirring was continued at room temperature overnight followed by 8 hours at reflux. Excess Grignard reagent was discharged by the cautious addition of 100 mL of saturated sodium bicarbonate solution. The resulting suspension was filtered through a bed of Celite, the filtrate diluted with 500 mL of ether and the combined organics washed several times with saturated sodium bicarbonate, once with brine and then dried for 1 hr over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was distilled twice from Na2CO3 through a base-washed 15 cm Vigreux (bp 65° C.@ 1 mmHg) to yield 39 g (32%) of the title alcohol as a clear, colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[O-:6][P:7]([O:10]P([O-])([O-])=O)(=[O:9])[O-:8].[Ca+2].[Ca+2]>>[P:7]([O-:10])([O-:9])([O-:8])=[O:6].[Ca+2:5].[P:7]([O-:10])([O-:9])([O-:8])=[O:6].[Ca+2:5].[Ca+2:5]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
On the other hand, the dry-type synthesizing method is a method in which calcium carbonate is reacted with calcium pyrophosphate in a solid phase at a high temperature thereby to obtain calcium phosphate powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1.[BH4-].[Na+].[OH-].[Na+]>CN(C=O)C.CO>[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH:35][CH2:12][C:10]3[CH:9]=[CH:8][C:5]4[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=4[N:11]=3)[CH2:32]2)=[N:27]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(n3)NC(=O)CO5)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (153 mg, 0.858 mmol) in DMF (1.36 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (84.4 mg, 0.286 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (37.6 mg, 0.572 mmol) was then added and the suspension was stirred for 1 h at RT. The reaction mixture was diluted with CH3OH and poured into 1 N NaOH. The organic layer was separated, washed with brine (4×), dried (Na2SO4), filtered, and concentrated. The crude material was purified by basic reverse phase HPLC to provide 4.6 mg (3.5%) of the title compound. MS (ESI): exact mass calculated for C24H23N7O3, 457.19; m/z found, 458.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.19 (d, J=8.0, 1H), 7.17 (d, J=9.1, 1H), 6.95 (d, J=8.0, 1H), 4.62 (s, 2H), 4.09 (s, 3H), 3.92 (s, 2H), 3.09-2.98 (m, 3H), 2.83-2.77 (m, 1H), 2.56 (dd, J=14.6, 7.9, 1H), 2.17-2.14 (m, 1H), 1.89-1.82 (m, 1H), 1.24 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:9]=[C:8]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](OCC3C=CC=CC=3)=[O:26])[CH2:20]2)[C:3]=1C(OC)=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:3]2[C:25](=[O:26])[N:21]3[CH2:20][CH:19]([CH2:24][CH2:23][CH2:22]3)[C:8]=2[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:11]=1
Reactant: COC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)cc(-c2ccccc2O)nc1N
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccc2O)cc2c1C(=O)N1CCCC2C1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 41.7 %

Procedure:
To a solution of methyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinate (60 mg, 0.130 mmol) in methanol (2.0 mL) and THF (1.0 mL) was added 10% Pd—C (200 mg). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 6.5 hrs. The mixture was filtrated on Celite®, and washed with MEOH and THF successively. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate, 2:1) to give 6-amino-4-(2-hydroxy-phenyl)-5,9-diazatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-8-one as a yellow solid (16 mg, yield; 40%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:25]5[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1csc(CO)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1csc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-methyl-2-thienyl)methanol (138 mg) and tributylphosphine (322 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg) in dry THF (5 ml). The mixture was stirred under sonication at 60° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (43 mg) as a white solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([F:69])[CH:63]=2)[C@@H:59]([C@H:70](O)[CH3:71])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([F:69])[CH:63]=2)[C@@H:59]([C@@H:70]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:71])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (216 mg, 0.65 mmol) in THF (10 mL) at 0° C. were added 5-chloro-pyridin-2-ol (58 mg, 0.45 mmol) and then DBAD (110 mg, 0.48 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (100 mg, 0.30 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 100 mg (75%) of the title compound as a colorless oil. ES-MS m/e: 445.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:29])[CH2:12][CH:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:14][C:15]=1[OH:16])[CH2:8][CH3:9])[CH3:4].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:30]([O:29][C:11]1[CH2:12][CH:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:14][C:15](=[O:16])[C:10]=1[C:7](=[N:6][O:5][CH2:3][CH3:4])[CH2:8][CH3:9])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(OC)cc(OC)cc2OC)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(OC)cc(OC)cc2OC)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Aqueous 1% sodium hydroxide solution (6.1 ml) was added to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethoxyphenyl)cyclohex-2-en-1-one (0.52 g; 1.40 mmole) in acetone (25 ml). The mixture was stirred at room temperature for a period of 5 minutes and then benzoyl chloride (0.21 g) was added dropwise. The mixture was stirred for a further period of 15 minutes and then the solvent was removed by evaporation under reduced pressure. The product was purified by chromatography over silica gel (eluant dichloromethane) to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-(2,4,6-trimethoxyphenyl)cyclohex-2-en-1-one (0.50 g; 73.9%) as a pale yellow solid, mp 139° C.
Reaction SMILES: C([O:3][C:4]([C:6](O)([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)=O)[C:7](OCC)=[O:8])=[O:5])C.O.[NH2:25][NH2:26].[OH-].[Na+].Cl>>[C:4]([C:6]1[C:7](=[O:8])[NH:25][N:26]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1)([OH:3])=[O:5]
Reactant: NN
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate (8.41 g, 25.8 mmol) inisopropanol (100 mL) was added hydrazine monohydrate (2.84 g, 56.8 mmol), and the mixture was heated under stirring at 100° C. for 6 hours. Then, 2 mol/L sodium hydroxide was added, and the mixture was stirred further at the same temperature for 4 hours. The reaction mixture was ice-cooled, and concentrated hydrochloric acid was added to acidify the system. The precipitate was collected by filtration, thoroughly washed with water and dried to yield the title compound as a slightly yellow crystalline powder (5.67 g, 87.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:18]([CH:22]1[CH2:23][CH:24]2[N:29]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]3[C:6]4[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][C:8]3=[O:11])[CH:27]([CH2:26][CH2:25]2)[CH2:28]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 68.6 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.219 g, 0.6 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc (4:1-4) gave the title compound (111MF26) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.16 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.0 Hz, J=9.0 Hz, 1H), 6.69-6.63 (m, 1H), 4.58 (q, J=14.8 Hz, J=38.0 Hz, 2H), 4.10-3.93 (m, 2H), 3.16-3.06 (m, 2H), 2.33 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.05 (t, J=11.6 Hz, 1H), 1.94-1.82 (m, 2H), 1.58-1.43 (m, 6H), 1.39-1.32 (m, 2H), 1.31-1.15 (m, 6H), 0.90-0.87 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 130.0 (d, J=10.4 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.5 Hz), 103.9 (d, J=28.9 Hz), 67.8, 61.9, 60.1, 58.2, 45.6, 38.6, 38.5, 36.9, 31.8, 29.4, 28.2, 27.4, 26.5, 23,1, 17.1, 14.3.