Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Brc1cccc2cnccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
5-Bromo-isoquinoline (100 mg, 0.48 mmol) was suspended in 0.58 mL of concentrated H2SO4. To this solution was added KNO3 (68 mg, 0.58 mmol) in 0.48 mL of concentrated H2SO4. The reaction mixture was stirred at room temperature for 1.5 hours, poured into water/ice, neutralized with 2.0 M Na2CO3, and extracted with EtOAc three times The combined organic layers were washed brine, dried (MgSO4), filtered and concentrated under vacuum to give 121 mg of the title product. MS (DCI) m/e 255 (M+H)+; 1H NMR (500 MHz, CDCl3) δ 10.0 (s, 1H), 9.39 (s, 1H), 8.85 (d, J=5.76 Hz, 1H), 8.17-8.22 (m, 2H), 8.12 (d, J=8.14 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]([CH:30]=O)[CH2:20]2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]([N:19]2[CH2:23][CH:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:21](/[CH:30]=[N:33]/[OH:34])[CH2:20]2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(/C=C/C(=O)N2CC(C=O)C(c3ccccc3)C2)ccc1-n1cnc(C)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C=CC(=O)N2CC(/C=N/O)C(c3ccccc3)C2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To an ethanol (2 ml) solution of (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acryloyl}-4-phenylpyrrolidine-3-carbaldehyde (34 mg) obtained in Example 358, hydroxylamine hydrochloride and sodium acetate were added, and the reaction solution was agitated at room temperature for 12 hours. After condensing reaction solution under reduced pressure, ethyl acetate and saturated sodium bicarbonate water were added, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, an elution solvent: ethyl acetate:methanol=10:1), and 16.2 mg (46%) of the title compound was obtained as a mixture of oxime moiety Z:E=1:2. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.S(=O)(=O)(O)O.O>C(OC(C)=O)CCC.C(O)CCC>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([O:10][CH2:2][CH2:3][CH2:4][CH3:5])=[O:9])[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCOC(=O)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.5 %

Procedure:
A solution of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (British patent no. 856409) (52 g, 0.33 mol) in nBuOAc (80 ml) and butanol (80 ml) was treated with concentrated sulphuric acid (5 ml). The mixture was heated at reflux under a Dean-Stark trap. After 5 hours water production had ceased. The reaction was allowed to cool to ambient temperature and after standing overnight, the precipitate was filtered, washed with diethyl ether and dried to give butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate as a white solid (55.2 g, 85%) m.p. 81-83° C.
Reaction SMILES: C(OC(N1CCC(C[NH:15][C:16]([C:18]2[S:28][C:27]3[N:29]4[C:20](=[CH:21][N:22]=[C:23]4[CH:24]=[CH:25][CH:26]=3)[CH:19]=2)=[O:17])CC1)=O)(C)(C)C.[ClH:30].[CH2:31](O)[CH3:32]>>[ClH:30].[ClH:30].[NH:22]1[CH2:23][CH2:24][CH:31]([CH2:32][C:21]2[N:22]=[C:23]3[N:29]4[C:27]([S:28][C:18]([C:16]([NH2:15])=[O:17])=[CH:19][C:20]=24)=[CH:26][CH:25]=[CH:24]3)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Reactant: CCO
Agent: Cl
Product: NC(=O)C1=Cc2c(CC3CCNCC3)nc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While 26.48 g (121.3 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 15.4 g (133 mM) of N-hydroxysuccinimide were stirred together in 250 ml of acetonitrile, 25.6 g (133 mM) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 6 hours. To this reaction mixture was added 20.3 ml (146 mM) of triethylamine as well as 27.3 g (127 mM) of 1-(tert-butoxycarbonyl)piperidin-4-ylmethylamine and the mixture was stirred at room temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9:1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide. To this crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added 30 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for one hour. To this reaction mixture was added ethanol, followed by stirring, and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(F)c(CO)cc1OC

Procedure:
A solution of 2-fluoro-4,5-dimethoxy-benzaldehyde (6.0 mmol) in MeOH (10 mL) was treated with NaBH4 (1.2 equiv.) at 0–23° C. for 0.5 h. After quenching with acetone and evaporating the solvent, work-up (CH2Cl2), drying (MgSO4) and evaporation gave the title compound as a crude oily product (94% yield). 1H-NMR (CDCl3): δ 6.90–6.88 (d, 1H), 6.61–6.64 (d, 1H), 4.65–4.63 (d, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.00–1.94 (t, 1H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:4]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[O:2]=[C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][NH:4]1
Reactant: CCOC(=O)c1cccc(Nc2cnc(OC)c3c2CCCC3)c1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc(Nc2c[nH]c(=O)c3c2CCCC3)c1
Yield: 40.7 %

Procedure:
560 mg (1.7 mmol) of ethyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino)benzoate (compound 12) are dissolved in 30 ml of chloroform and, at room temperature, 413 mg (2.1 mmol) of trimethylsilyl iodide are added. The mixture is then heated to reflux until complete conversion is reached by means of LCMS. Further trimethylsilyl iodide is added if necessary. For workup, the mixture is washed twice with H2O, dried with Na2SO4 and concentrated. Chromatography on silica gel (CH2Cl2/MeOH 95:5) affords 216 mg of the title compound. Yield: 40%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)cn1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cn1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-methoxypyridine-3-carbaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 500.
Reaction SMILES: [S:1]([O:5][C@H:6]1[C@@H:12]([CH2:13][O:14][C:15]([O:17][CH3:18])=[O:16])[O:11][CH:8]([O:9][CH3:10])[C@@H:7]1[OH:19])([CH3:4])(=[O:3])=[O:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>N1C=CC=CC=1>[S:1]([O:5][C@H:6]1[C@@H:12]([CH2:13][O:14][C:15]([O:17][CH3:18])=[O:16])[O:11][CH:8]([O:9][CH3:10])[C@@H:7]1[O:19][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)OC[C@H]1OC(OC)[C@H](O)[C@H]1OS(C)(=O)=O
Solvent: c1ccncc1
Product: COC(=O)OC[C@H]1OC(OC)[C@H](OC(=O)c2cccc(C(F)(F)F)c2)[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
A flame dried 250 ml flask equipped with an addition funnel, magnetic stirrer and nitrogen inlet was charged with methyl 3-O-mesyl-5-O-(methoxycarbonyl)-D-xylofuranoside (5.84 g, 19.4 mmoles) (C. D. Anderson, L. Goodman and B. R. Baker, J. Am. Chem. Soc. 1958, 80, 5247) and anhydrous pyridine. The solution was cooled in an ice bath and 3-(trifluoromethyl)-benzoyl chloride (5.27 g, 25.3 mmoles) was added dropwise over 10 min. After the addition was complete the ice bath was removed and the reaction was continued 24 hours at ambient temperature. The mixture was poured into ice water (400 mL) and the aqueous solution extracted with ether (2×250 mL). The combined ether extracts were washed with 400 mL. of 1.2NHCl and 400 mL of 10% aqueous NaHCO3. The solvent was removed by rotary evaporation and the residual oil was purified by flash chromatography (3-inch diameter column containing 18 inches of flash silica gel). The column was eluted with 1:1/ethyl acetate:hexanes while collecting 200 mL fractions. Fractions 12-15 contained pure product and these fractions were concentrated in vacuo to afford 8.92 g (97.3%) of methyl 3-O-mesyl-5-O-(methoxycarbonyl)-2-O-(m-trifluoromethylbenzoyl)-D-xylofuranoside as a colourless oil containing an approximately equal mixture of α and β anomers. 1H NMR (CDCl3) δ3.09 and 3.19(s, 3H, OCH3), 3.34 and 3.37(s, 3H, SO2CH3), 3.79(s, 3H, OCO2CH3), 4.4-4.9(m, 3H, C-4H and C-5H), 5.1-5.6(m, 3H, C-1H, C-2H and C-3H) and 7.5-8.5 (m, 4H, ArH); TLC Rf =0.77 and 0.84, silica gel, CHCl3 :CH3OH/90:10.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][N:9]=1
Reactant: O=C(NCCc1ccccc1)c1ccccc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccccc1C1=NCCc2ccccc21
Temperature: 100 °C

Procedure:
A suspension of 50.0 g (164 mmol) of N-phenylethyl-2-bromobenzamide and 27.9 g of phosphorus pentoxide in 200 ml of xylene was heated to 100° C. and admixed dropwise with 45.6 g (492 mmol) of phosphorus oxychloride. Subsequently, the reaction mixture was heated under reflux for 2 h. After cooling to 80° C., the reaction mixture was stirred into 4000 g of ice and adjusted to pH=12 with NaOH (solid). The organic phase was removed, the aqueous phase was extracted three times with 300 ml of toluene, and the combined organic phases were washed with 500 ml of water and subsequently dried over magnesium sulfate. After the desiccant had been filtered off and the solvent had been removed, the product was obtained as a yellow oil. The yield at a purity of approx. 99.0% was 46.9 g (164 mmol), 99.9% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[N:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[N:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)nn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCO)CC4)nn3)nc2n1C1CCCC1
Yield: 12.7 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(6-piperazin-1-yl-pyridazin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 2-bromo ethanol (143 mg, 1.14 mmol) gave 7-cyclopentyl-2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridazin-3-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (14 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a solution of ethyl 2-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.61 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.088 g, 0.61 mmol) in ethanol (10 mL), piperidine (0.0044 mL, 0.044 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.061 g, y. 23%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:21][N:22]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNN>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:21][NH2:22])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O[C@@H](CCOCc1ccccc1)COCc1ccccc1
Agent: CNN
Solvent: ClCCl
Product: NO[C@@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A solution of (S)-N-(1,4-dibenzyloxybut-2-oxy)phthalimide (5 g, 11.6 mmol) in dichloromethane (50 ml) was treated with methylhydrazine (0.8 ml, 15 mmol). A deep red colouration developed, disappearing gradually as a white solid precipitated out of solution. After stirring at room temperature for 1 hour, the solid was filtered off and the filtrate was washed with a 3% sodium carbonate solution. After drying (MgSO4) the solution was evaporated to dryness and the residual oil was chromatographed on silica eluting with ethyl acetate-hexane 5:1 to give (S)-1,4-dibenzyloxybut-2-oxyamine (2.66 g, 76%), [α]D25 -3.2° (c 0.3 in ethanol); IR: υmax (film) 3315, 3248, 3087, 3062, 3030, 2922, 2861, 1588, 1496, 1454, 1365, 1205, 1101, 1028, 738, 698 cm-1 ; 1H NMR: δH (CDCl3) 1.85 (2H, m, CH2), 3.55 (4H, m, 2×CH2), 3.90 (1H, m, CH), 4.49 (2H, s, CH2), 4.55 (2H, s, CH2), 5.36 (2H, s, D2O exchangeable NH2), 7.30 (10H, m, 2×C6H5); m/z 302 (MH+), 301 (M+, 3%), 181 (5), 163 (10), 106 (15), 105 (5), 92 (15), 91 (100), 71 (15), 65 (10). Found: C, 71.40; H, 7.66, N, 4.61%, M+ 301.1670. C18H23NO3 requires: C, 71.73; H, 7.69, N, 4.65% M+ 301.1678.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:41][CH:42]([CH3:44])[CH3:43])[CH2:30][CH2:29]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (51 mg, 0.082 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 7.12 μmol) in THF (820 μL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (41.2 mg, 95%) as a yellow foam. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.88-1.98 (m, 2H), 2.05-2.14 (m, 2H), 2.94-3.03 (m, 4H), 3.35-3.43 (m, 2H), 3.54 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 4.10-4.21 (m, 3H), 4.32-4.39 (m, 1H), 6.67 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 416.3.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[C:24]([CH3:37])=[C:25]([CH2:29][NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:26]=[N:27][CH:28]=1>>[CH3:37][C:24]1[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)=[CH:28][N:27]=[CH:26][C:25]=1[CH2:29][NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cc1c(Br)cncc1CN[S@](=O)C(C)(C)C
Product: Cc1c(CN[S@](=O)C(C)(C)C)cncc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
In analogy to the procedure described for the preparation of example 45, 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to (R)-2-methyl-propane-2-sulfinic acid (5-bromo-4-methyl-pyridin-3-ylmethyl)-amide (intermediate A-59) to give the title compound as a colorless amorphous solid. MS: 386.5 (M+H+).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:28]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][C:22]=4[N:21]([CH3:36])[C:20]=3[N:37]=2)[C:12](=[O:38])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[N:21]([CH3:36])[C:20]=3[N:37]=2)[C:12](=[O:38])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.25 M HCl in MeOH (4 mL) was added to tert-butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.12 g, 0.24 mmol) and the resulting solution was stirred under N2 at ambient temperature for 18 h. The solution was concentrated to dryness to provide the title compound (0.11 g, quant.) as an orange solid: mp 180-185° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.02 (d, J=8.5 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 4H), 7.38 (d, J=7.5 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.16 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.73 (s, 3H), 3.39-3.38 (m, 2H), 3.33-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.14 (t, J=5.5 Hz, 2H); ESI MS m/z 401 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.9 min.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:33][CH2:32][C:6]2([N:10]([O:11][CH2:12][CH2:13][S:14][CH3:15])[C:9](=[O:16])[C:8]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:7]2[O:26][C:27](=[O:31])[O:28][CH2:29][CH3:30])[CH2:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:42])C=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:15][S:14]([CH2:13][CH2:12][O:11][N:10]1[C:6]2([CH2:5][CH2:4][N:3]([O:2][CH3:1])[CH2:33][CH2:32]2)[C:7]([O:26][C:27](=[O:31])[O:28][CH2:29][CH3:30])=[C:8]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[C:9]1=[O:16])=[O:42]
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OCCSC)C12CCN(OC)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OCCS(C)=O)C12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of carbonic acid ethyl ester 8-methoxy-1-(2-methylsulfanyl-ethoxy)-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (compound P1ii.110) (400 mg, 0.84 mmol) in dichloromethane (10 ml) at 0° C. was added 3-chloroperbenzoic acid (210 mg, MCPBA ˜70%, 0.85 mmol). The reaction mixture was stirred at room temperature overnight, then poured on saturated aqueous sodium metabisulfite and the layers separated. The aqueous phase was extracted with dichloromethane (3×), the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol 20:1). Yield: 220 mg of carbonic acid ethyl ester 1-(2-methanesulfinyl-ethoxy)-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.111) as a colorless gum.
Reaction SMILES: [CH:1]1([CH:7]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH2:8]OC2C=CC(C(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:48]=[C:47]([F:49])[C:46]([OH:50])=[C:45]([F:51])[CH:44]=1>>[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:44]=[C:45]([F:51])[C:46]([O:50][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[C:47]([F:49])[CH:48]=1
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2ccc(C(=O)O)cn2)C2CCCCC2)c(OC)n1
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethanol (Example 73, intermediate b), 3,5-difluoro-4-hydroxy-benzoic acid methyl ester (commercially available), tri-N-butylposphine and N′N′N′N-tetramethylazodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:tert-butyl methyl ether (100:0 to 50:50). Off-white foam (45%). MS (Turbo Spray): m/z=588.3 [M+H].