Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O.O>[Cl:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1Cl)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 62 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13].[C-]#N.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[OH:13][NH:12][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: NO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To methyl phenylacetate (0.288 mL, 2.0 mmol) in THF:MeOH: 50% aqueous NH2OH (1:1:0.5, 2.5 mL) was added KCN (5 mg, 0.08 mmol, 4 mol %) and the mixture was stirred at ambient temperature. After 2 h the reaction was complete by HPLC. To the mixture was added saturated aqueous citric acid (25 mL) followed by extraction with EtOAc (3×25 mL). The organic phase was isolated, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase HPLC (C-18, 5μ 100×30 mm column), eluting with a gradient of acetonitrile: water (0.05% TFA). Following lyophilization of the product fractions there was obtained pure N-hydroxy-2-phenylacetamide as a fluffy solid (0.234 g, 77% yield): LRMS (M+H)+: 152.1 m/z; 1H NMR (DMSO-d6) δ: 10.6(s, 1H), 8.81(s, 1H), 7.2(m, 5H), 3.26(s, 2H); Anal (C,H,N): % C: (calc) 63.56; (found) 63.63; % H: (calc.) 6.00; (found) 5.91; % N: (calc.) 9.27, (found) 9.04.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(CCC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC1CCN(CCC(=O)O)CC1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of benzyl 3-(4-acetamidopiperidin-1-yl)propanoate (3.81 g, 12.5 mmol) and Pd/C (10%, 0.20 g) in methanol (100 mL) was stirred under hydrogen atmosphere overnight. The solid was filtered and the filtrate was evaporated to give 3-(4-acetamidopiperidin-1-yl)propanoic acid (2.50 g). LCMS (+ESI) 215 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8]CC(N(C)C)=O)=[O:7])=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:3]=1.CO.O.[OH-].[Li+].Cl>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:3]=1
Reactant: CN(C)C(=O)COC(=O)c1ccc(Cl)cc1OCC(=O)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Yield: 159.6 %

Procedure:
The product from step (a) (1.0 g) was dissolved in a 2:1 water:methanol mixture (15 ml) and lithium hydroxide monohydrate added. After 2 hours 2M aqueous hydrochloric acid and ethyl acetate were added, the organic phase separated, dried and concentrated to give the product as a solid (1.2 g), m.p. 141-142° C.
Reaction SMILES: [Cl:1][CH:2]1[CH:16]([CH3:17])[C:6]2[C:7](=[O:15])[CH:8]=[C:9]([O:13]C)[C:10](=[O:12])[NH:11][C:5]=2[CH2:4][CH:3]1[Cl:18].B(Br)(Br)Br.C([O-])(O)=O.[Na+].[K+].[Br-]>C(Cl)Cl>[Cl:1][CH:2]1[CH:16]([CH3:17])[C:6]2[C:7](=[O:15])[CH:8]=[C:9]([OH:13])[C:10](=[O:12])[NH:11][C:5]=2[CH2:4][CH:3]1[Cl:18]
Reactant: COc1cc(=O)c2c([nH]c1=O)CC(Cl)C(Cl)C2C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: CC1c2c([nH]c(=O)c(O)cc2=O)CC(Cl)C1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 7,8-dichloro-3-methoxy-6-methyl-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione (120 mg, 413 μmol) in dry CH2Cl2 (20 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (2.5 mL, 1M, Aldrich) in one portion over 5 seconds at rt. The suspension immediately turned green. The reaction was allowed to stir under N2 at rt for 1 h. The reaction was added to saturated NaHCO3 (50 mL) and the resulting pale pink suspension was vigorously stirred for 15 min to give an emulsion. The emulsion was vacuum filtered and the resulting pink aqueous solution washed with CH2Cl2 (1×10 mL). The aqueous portion was acidified with concd HCl (pH 2). The resulting precipitate was collected by filtration and washed to neutrality with water (6×2 mL). Crystallization of the damp filter cake from 95% EtOH (dissolved in boiling solvent (45 mL), hot filtered, allowed to cool to rt) yielded a colorless, fluffy solid (67 mg, 59%, pure by 1H NMR, probable mixture of diastereomers (9 to 1)); mp 180°-181° C. (dec.); 1H NMR (DMSO-d6 and D2 O) δ1.17 (d, J=6.9 Hz, 3H), 2.97 (dd, J1 =17.4 Hz, J2 =9.6 Hz, 1H), 3.13 (dd, J1 =17.4 Hz, J2 =4.8 Hz, 1H), 3.22 (m, 1H), 4.13 (dd, J1 =9.3 Hz, J2 =6.6 Hz, 1H), 4.38 (m, 1H), 6.32 (s, 1H), the spectrum without D2O shows additional resonances δ10.47 (bs, 1H), 11.01 (s, 1H); IR (KBr) 3301 (m), 3207 (w), 3165 (w), 3093 (m), 2987 (m), 1680 (m), 1648 (m), 1613 (m), 1553 (s), 1463 (w), 1447 (w), 1425 (w), 1401 (m), 1345 (m), 1319 (w), 1285 (m), 1227 (m), 1164 (w), 1123 (w), 1054 (w), 1020 (w), 934 (w), 911 (m), 861 (w), 810 (m), 770 (m), 754 (m), 717 (m), 667 (w), 656 (w), 621 (w), 494 (w) cm-1 ; Anal. Calcd for C11H11Cl2NO3 : C, 47.85, H, 4.02, N, 5.07. Found: C, 48.00; H, 3.85; N, 5.20. ##STR155## The binding data imply that compounds of Formula IX having a combination of substituents other than H at R1, R3 and R4 are preferred.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:13]=2)[N:3]=1.[CH:19]1([C:22]2([C:28]#[N:29])[CH2:26][CH2:25][NH:24][C:23]2=[O:27])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:19]1([C:22]2([C:28]#[N:29])[CH2:26][CH2:25][N:24]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:13]=4)[N:3]=3)[C:23]2=[O:27])[CH2:21][CH2:20]1
Reactant: CC(C)(CO)n1cc(Nc2nccc(Cl)n2)cn1
Reactant: N#CC1(C2CC2)CCNC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(CO)n1cc(Nc2nccc(N3CCC(C#N)(C4CC4)C3=O)n2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a mixture of 2-(4-((4-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (200 mg) obtained in Step E of Example 347, 3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (110 mg) obtained in Step C of Example 103, cesium carbonate (490 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26 mg) in toluene (2.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (14 mg), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: C1C=CC([P:7]([Cl:10])([Cl:9])=[O:8])=CC=1.[P:11]([Cl:14])([Cl:13])[Cl:12]>>[P:11]([Cl:14])([Cl:13])[Cl:12].[P:7]([Cl:10])([Cl:12])([Cl:9])=[O:8]
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: ClP(Cl)Cl
Product: O=P(Cl)(Cl)Cl
Temperature: 600 °C

Procedure:
100 g (=0.513 mol) of phenylphosphonyl dichloride and 200 g (=1.45 mol) of phosphorus trichloride were mixed. This mixture was introduced dropwise, over the course of 3 hours, into a vertical quartz tube which was 60 cm long, filled with 6 mm diameter quartz Raschig rings, was flushed with nitrogen and was located in an electric oven heated to 600° C. The reaction mixture collecting in the trap was again introduced dropwise, over the course of 2 hours, into the quartz tube at 600° C. The reaction mixture now produced was distilled in vacuo. Apart from unreacted phosphorus trichloride and phosphorus oxychloride, 80 g of a distillate were obtained which, on the basis of a 31P NMR spectrum, had the following composition:
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1CSc2ccccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1CSc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4-benzothiazine-3(4H)-one (1.0 g, 6.05 mmol) and Cs2CO3 (2.96 g, 9.08 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.37 g, 6.66 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.45 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a slightly yellow oil. Yield 1.37 g, 90.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): d 2.14 (m, 2H), 3.38 (s, 2H), 3.36 (t, 2H), 4.17 (t, 2H), 7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37 (d, 1H). 13C NMR (CDCl3): d 30.61, 31.81, 42.48, 42.66, 117.87, 123.78, 124.29, 127.52, 127.52, 128.78, 139.40, 165.51
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[Cl:23][CH:24]([Cl:28])[C:25]([OH:27])=[O:26]>>[Cl:23][C:24]([Cl:28])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)c1ccc(OCCCCCCCCCCBr)cc1
Reactant: O=C(O)C(Cl)Cl
Product: CC(C)(C)c1ccc(OCCCCCCCCCCC(Cl)(Cl)C(=O)O)cc1
Yield: 33.5 %

Procedure:
6.8 g (20 mmol) 92 was reacted with 10.3 g (80 mmol) dichloroacetic acid as in example 9. 2.8 g (35%) 41 with a melting point of 56-57° C. was obtained. The sodium salt obtained from 41 and pulverized NaOH in ethanol melted at 178° C. (decomp.).
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][C@H:18]([OH:28])[CH2:19][NH:20]C(OC(C)(C)C)=O)([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:29]>C(OCC)(=O)C>[ClH:29].[C:1]1([O:7][P:8]([CH2:17][C@H:18]([OH:28])[CH2:19][NH2:20])([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)Oc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@@H](O)CP(=O)(CC1CCCCC1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid phenyl ester (495 mg, 1.2 mmol) in ethyl acetate (10 mL) was bubbled in HCl gas until saturated, via a pipette at a rate such that the temperature did not exceed 10° C. Once saturated, the reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The resulting residue was triturated with ether (100 mL) and the resulting solid collected to give ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid phenyl ester hydrochloride (248 mg, 0.71 mmol). 1H-NMR (CD3OD, 300 MHz): δ 7.35 (m, 2H), 7.18 (m, 3H), 4.18 (br s, H), 3.21-3.09 (m, 2H), 2.01-1.58 (m, 10H), 1.43-0.95 (m, 9H). 31P NMR (CD3OD, 300 MHz): 57.12, 57.47. LC/MS m/z: [M+H]+=312.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:26](O)=[O:27].O1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[CH2:26][OH:27]
Reactant: COc1ccc(Cc2ncc(C(=O)O)c3cc(OC)c(OC)cc23)cc1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A slurry of 25.2 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid and 100 ml of dry tetrahydrofuran was stirred at 15° in an inert atmosphere while cautiously adding 200 ml of 1 molar borane/tetrahydrofuran complex. After stirring for 2 hours at room temperature, the initial solids had dissolved and were replaced by a second precipitate. The mixture was cautiously treated with 200 ml of water and the tetrahydrofuran was removed in vacuo at 40°. The chilled reaction mixture was then filtered, washed with water, and the damp stable borane complex was added portionwise with stirring to 200 ml of 2N hydrochloric acid previously heated to 70°-80°. The resulting solution was heated an additional 15 minutes on the steam bath and was then chilled and extracted with 100 ml of diethyl ether. The aqueous layer was added dropwise to 250 ml of cold 2N sodium hydroxide with stirring. The resulting solids were removed by filtration, washed well with water, and dried to give 20.6 g of crude 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol, mp 146°-148°. Recrystallization from methylene chloride/ethyl acetate gave 19.2 g of purified 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol, mp 141°-143°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][C:16]([Cl:20])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH2:21]([OH:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:18]1[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:11])=[O:10])=[N:14][CH:15]=[C:16]([Cl:20])[N:17]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: CCCCO
Product: CCCCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using 1-butanol (0.05 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.1 g). Yield 0.037 g.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:23][C:24]1[N:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:28]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([N:27]5[CH:28]=[C:24]([CH3:23])[N:25]=[N:26]5)[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Cc1cn(C2CCNC2)nn1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: CC#N
Product: Cc1cn(C2CCN(c3c(F)c(C)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1

Procedure:
A suspension of 50 mg (0.168 mmol) of 1-cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-(4-methyl-1,2,3-triazol -1-yl)pyrrolidine hydrochloride (79 mg, 0.421 mmol) and 64 mg (0.421 mmol) of DBU (diazabicyloundecane) in dry acetonitrile (5 ml) was refluxed under nitrogen for 46 h. The yellow solution was concentrated to dryness and the residue was triturated with acetonitrile and thus separated solid was filtered. The supernatant was evaporated to dryness and water was added to the residue and separated solid was collected (30 mg, 43%), m.p. 232°-234° C. 1H NMR (TFA) δ: 9.26 (s, 1H), 8.37 (s, 1H), 5.78-5.58 (m, 1H) 4.85-4.1 (m, 5H), 3.0-2.7 (m, 5H), 2.68 (s, 3H), 1.65-1.15 (m, 4H). Anal. calcd. for C21H21F2N5O3 : C, 58.74; H, 4.93; N, 16.31. Found: C, 58.14; H, 5.06; N, 16.08.
Reaction SMILES: [C:1]([C:3]([CH3:29])([CH3:28])[C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)#[N:2].C1(C)C=CC=CC=1.C[Si]([N:41]=[N+:42]=[N-:43])(C)C.C[Sn](=O)C>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:9][CH2:8][C:7]2[CH:26]=[CH:27][C:4]([C:3]([CH3:29])([C:1]3[NH:43][N:42]=[N:41][N:2]=3)[CH3:28])=[CH:5][CH:6]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: CC(C)(C#N)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Sn](C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1)c1nnn[nH]1
Temperature: 95 °C

Procedure:
N-[4-(Cyano-dimethyl-methyl)-benzyl]-2-(4-fluoro-phenoxy)-nicotinamide (12.22 g) was placed in a sealable tube with anyhdrous toluene (10 mL). Trimethylsilyl azide (8.0 mL) and dimethyltin oxide (1.29 g) were then added. The reaction mixture was heated to 95° C. for 17 h, then allowed to cool to ambient temperature. Excess methanol was added and the mixture was concentrated to dryness in vacuo. Methanol was again added and evaporated. To the crude product were added ethyl acetate (200 mL) and and saturated aqueous sodium bicarbonate (100 mL) and water (100 mL). The aqueous layer was collected, and the organic layer extracted with 50% sodium bicarbonate twice (100 mL). The combined aqueous portions were separated and brought to pH 3 with conc. hydrochloric acid. The aqueous solution was then re-extracted with ethyl acetate (5×300 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by recrystallization (ethanol) to yield the title compound (5.36 g).
Reaction SMILES: C[O:2][C:3]1([O:12][CH3:13])[CH2:8][CH:7]([CH3:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]1.[CH3:14][C:15]([O:20]O)([CH3:19])[CH2:16][CH2:17][CH3:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>[CH3:13][O:12][C:3]1([O:2][O:20][C:15]([CH3:19])([CH3:14])[CH2:16][CH2:17][CH3:18])[CH2:8][CH:7]([CH3:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]1
Reactant: COC1(OC)CC(C)CC(C)(C)C1
Reactant: CCCC(C)(C)OO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: CCCC(C)(C)OOC1(OC)CC(C)CC(C)(C)C1
Yield: 92.2 %

Procedure:
A mixed solution consisting of 20.7 g of dimethyl sulfoxide and 1.6 g of p-toluenesulfonic acid was kept at 20° C., to which was added dropwise another mixed solution consisting of 37.3 g of 3,3,5-trimethyl-cylcohexanone-dimethylacetal and 23.8 g of 1,1-dimethylbutyl hydroperoxide. The resulting solution had an acid concentration of 0.1 mol/kg of the solution. The solution was treated in the same manner as described in Example 1 to obtain 50.3 g (yield: 68%) of crude 1-methoxy-1-(1,1-dimethylbutylperoxy)-3,3,5-trimethylcyclohexane having a purity of 75%. The resulting crude peroxyketal was distilled at 68°-72° C. under a vacuum of 0.005 mmHg to obtain a purified peroxyketal having a purity of 96%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:21])[CH2:19][CH3:20])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reacted with 23 μL of propionyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:19])[CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[Br:20].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:19])[CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[Br:20]
Reactant: Nc1c(F)cc(C(=O)CNC2CCCCC2)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(F)cc(C(O)CNC2CCCCC2)cc1Br

Procedure:
m.p. of the hydrochloride: 191°-195° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-cyclohexylamino-5'-fluoroacetophenone and sodium borohydride analogous to Example 49.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([CH2:31][OH:32])[CH:16]=2)=[C:11]([F:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:31]=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CO)c12
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C=O)c12
Yield: 100.5 %

Procedure:
1.10 g of [6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanol were dissolved in 5 ml of dichloromethane. At 0° C. 0.52 g Dess-Martin-Periodinane were added. After 16 h at r.t. the reaction was diluted with dichloromethane, and washed subsequently with 1 N aqueous hydrochloric acid and sat. aqueous sodium hydrogencarbonate solution. The organic layer was then dried over sodium sulphate, filtered and concentrated in vacuo to yield 1.10 g (100%) of the crude title compound, which was used without further purification in the next step.