Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.BrN1C(=[O:30])CCC1=O.C([O-])(O)=O.[Na+].O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:30])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Yield: 95 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (118.7 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). The obtained yellow solution was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHCO3 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 110.8 mg (95%) of crude N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) which contained 77% of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area %=99.6) with Tm=140-141° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][NH:24][CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].CO>C(Cl)Cl>[C:35]([N:24]1[CH2:25][CH2:26][C:27]2[N:28]=[C:20]([NH:19][C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:8]4[C:9]5[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=5)[CH2:6][CH2:7]4)[CH2:16][CH2:15]3)=[O:18])[S:21][C:22]=2[CH2:23]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1nc2c(s1)CNCC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(6-fluoroindolin-1-yl)-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperidine-1-carboxamide, prepared as in Example 19 above (51.6 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added pyridine (0.5 mL) and then acetyl chloride (0.014 mL, 0.2 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 15 min and then MeOH (1 mL) was added. The resulting mixture was continuously stirred for 15 min and concentrated. The resulting residue was purified by column using EtOAc as the eluent to yield N-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-(6-fluoroindolin-1-yl)piperidine-1-carboxamide.
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][C:5]([CH2:14][C:15]([O-:17])=O)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][C:5]([CH2:14][C:15]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:17])=[N:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: COc1nc(CC(=O)[O-])nc(N2CCOCC2)c1F
Reactant: CC1Cc2ccccc2N1
Agent: [Na+]
Product: COc1nc(CC(=O)N2c3ccccc3CC2C)nc(N2CCOCC2)c1F

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 600 mg of sodium (5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetate obtained in example 1a (step 4a) and 272 mg of 2-methyl-2,3-dihydro-1H-indole. After purification by silica column chromatography (eluent: 97/03 dichloromethane/ethyl acetate), 366 mg of 2-(5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)-1-(2-methyl-2,3-dihydroindol-1-yl) ethanone are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.3 %

Procedure:
To a mixture of ethyl 3-[{[4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (197 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 7 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (161 mg, 87%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:14][CH2:15]2)[S:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC2CCN(C3CCCCC3=O)CC2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(c2cccc(OC)c2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=551.4 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 3-methoxy-aniline, and yielded (+/−)-trans-2-[4-(3-methoxy-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(3-methoxy-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(3-methoxy-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.CCN(CC)CC>[C:24]1([S:30]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]([C:15]3[CH:20]=[CH:19][C:18]([O:21][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])=[CH:17][CH:16]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:22])([F:23])[F:1])=[CH:13][CH:12]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C(c2ccc(OS(=O)(=O)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Yield: 89.2 %

Procedure:
An oven-dried 100 ml 3-necked flask is equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, and is charged with 4,4'-(hexafluoroisopropylidene)diphenol (Aldrich) (5.45 grams, 16.2 mmol), 4-dimethylaminopyridine (0.4 gram, 3.3 mmol), and anhydrous Et3N (40 ml). The solution is stirred and treated slowly with benzenesulfonyl chloride (4.7 ml, 36.8 mmol) via syringe. The resulting mixture is heated at reflux for 9 hours. Workup consists of partitioning the reaction mixture between CH2C2 (100 ml) and a mixture of H2 (150 ml) and concentrated HCl (40 ml), washing the organic phase successively with 100 ml portions of H2O, 5 percent NaOH, H2O and saturated brine, drying (MgSO4), filtration and concentration. This gives 10.6 grams of a reddish oily residue. TLC analysis on silica gel shows one main component (Rf =0.54; CH2Cl2). Chromatography on a column packed with flash-grade silica gel (3"×1" i.d.), eluting with CH2Cl2, gives 9.32 grams of a faintly yellowish oil, which solidifies on standing. Recrystallization from EtOAc-MeOH-H2O (20 ml:100 ml:10 ml)affords 8.91 grams (89 percent yield) of the title compound as a white crystalline solid, m.p. 133° C. to 134° C.
Reaction SMILES: [CH3:1][C:2]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[C:3]#[CH:4].C([Li])CCC.CN([CH:19]=[O:20])C.OP([O-])(O)=O.[K+]>C1COCC1.C1CCCCC1.CCOCC>[CH3:1][C:2]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[C:3]#[C:4][CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C#CC=O)O[Si](C)(C)C
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Dissolve 3-methyl-3-trimethylsilyloxy-1-butyne (8.35 g, 53.4 mmol) in THF (200 mL) and cool to 40° C. Add n-butyllithium (26.7 mL of a 2.0 M solution in cyclohexane, 53.4 mmol, 1 eq.) dropwise over a 5 minute period. Stir for 10 min., then add dry DMF (8.27 mL, 7.81 g, 107 mmol, 2 eq.) in one portion. After 30 min., pour into a cooled (0° C.), vigorously stirred mixture of 10% KH2PO4 (290 mL, 213 mmol) and ether (300 mL). Separate the layers and wash the organic layer with water (2×200 mL). Dry (MgSO4), filter, and concentrate to give 9.4 g (94% crude) of a light oil. Use without further purification. TLC: Rf=0.40 (20:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ 9.03 (s, 1H), 1.35 (s, 6H), 0.02 (s, 9H).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:3][CH2:2]1.O1[CH2:22][CH2:21][CH2:20][CH2:19]1.CO.[C:25]([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:19][CH:20]([CH3:25])[CH2:21][CH2:22][N:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)[CH2:12][CH2:13]1
Reactant: c1ccc2c(c1)SCCC2N1CCCNCC1
Reactant: C1CCOC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CCN1CCCN(C2CCSc3ccccc32)CC1

Procedure:
A dry 100 ml 3-necked flask under nitrogen was charged with N-(3,4-dihydro-2H-benzothiopyran-4-yl)homopiperazine (1.0 g; 4.03 mmol) and treated sequentially with tetrahydrofuran (20 ml), methanol (10 ml), isoamyl aldehyde (5.0 ml; 46.0 mmol), sodium cyanoborohydride, (0.40 g; 6.4 mmol) and acetic acid (0.4 ml) as in Example 3. The resulting material was purified by kugelrohr distillation to give an oil (1.09 g), bp (air bath temperature) 150°-160° C. at 200 mtorr; 1H NMR (300 MHz, CD3OD) δ0.88-0.90 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:12]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[C:8]([Cl:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: ClCl
Reactant: O=Cc1c(O)ccc(Cl)c1F
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1c(O)c(Cl)cc(Cl)c1F
Temperature: 60 °C
Yield: 85.3 %

Procedure:
To 20 g (114.6 mmole) of 3-chloro-2-fluoro-6-hydroxybenzaldehyde in 250 mL of glacial acetic acid was added 27.8 g of Cl2 gas over a period of 30 min. The mixture was stirred and heated to 60° C. for 2 hrs and allowed to stir at rt overnight. The reaction mixture was diluted with 1L of water and extracted four times with diethyl ether. Combined extracts were washed with water and sat. brine and concd in vacuo to afford a slurry. Addition of 250 mL of water afforded a solid which was collected by filtration and allowed to air dry for 8 hrs to afford 20.42 g (85%) of a yellow solid: mp 58-62° C.; 1H NMR (CDCl3/400 MHz) 7.65 (d, 1H, J=7.5 Hz), 10.26 (s, 1H), 11.88 (s, 1H); 13C NMR (CDCl3/100 MHz) 111.2 (d, J=12.0 Hz), 118.2 (d, J=4.6 Hz), 127.8, 137.6 (C—H, d, J=2.1 Hz), 156.8 (d, J=3.0 Hz), 158.3 (d, J=260.8 Hz), 191.4 (CHO, d, J=8.8 Hz); 19F NMR (CDCl3/400 MHz) −124.7 (d, 1F, J=7.7 Hz); MS (EI) 208 (M+, 100); 207 (91); HRMS (EI) m/z calcd for (C7H3O2Cl2F) 207.9494, found 207.9470.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=3[CH2:11]2)=[O:9])[CH:4]=1.N1CC[CH:26]([OH:29])C1.CCN(CC)CC>C(Cl)Cl>[OH:29][CH:26]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([C:20]([F:21])([F:23])[F:22])=[CH:13][C:12]=3[CH2:11]2)=[O:9])[CH2:4]1
Reactant: C[n+]1ccn(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)c1
Reactant: OC1CCNC1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of 1-methyl-3-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-3H-imidazol-1-ium iodide (preparation #3) (0.046 g, 0.10 mmol) in DCM (1 mL) was added pyrrolidin-3-ol (0.009 g, 0.10 mmol) and Et3N (0.014 mL, 0.10 mmol) and the reaction mixture was shaken at ambient temperature for about 30 min. The reaction mixture was dried in vacuo (Genevac®) and the residue purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 10% to 65% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford (3-hydroxy-pyrrolidin-1-yl)-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (0.011 g, 33%). RP-HPLC (Table 1, Method a) Rt 1.72 min; m/z: (M+H)+ 316.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[CH3:20]>CC(C)=O.CN(C=O)C>[CH2:19]([N:21]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:24][CH:23]=1)[CH3:20]
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCNc1ccc(C(C)C)cc1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(c1ccc(C(C)C)cc1)c1nc(=O)c2cccnc2s1
Yield: 68.9 %

Procedure:
The reaction procedure of Example 85 was followed except that 2.347 g (15.1 mmol) of 2-chloronicotinic acid, 30 ml of thionyl chloride, three droplets of DMF, 1.262 g of ammonium thiocyanate, 15 ml of acetone, 2.583 g of N-ethyl-4-isopropylaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from a mixture of ethanol, ether and hexane to obtain 3.388 g of 2-[N-ethyl-N-(4-isopropylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1.C(OC(=O)C)C.[ClH:38].C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.[ClH:38]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(N)O
Reaction time: 1.5 h

Procedure:
The Boc-aminopropanol-fenbufen obtained above (1.82 mmol) was dissolved in dichloromethane (4 ml), and under ice-cooling, 4 N hydrochloric acid ethyl acetate solution (4 ml) was added thereto, and then the mixture was gradually returned to room temperature and stirred for 90 minutes. Precipitation of white precipitate was observed just after the commencement of the reaction. After confirming disappearance of Boc-aminopropanol-fenbufen by TLC, diethyl ether was added to the reaction solution, and the resulting white precipitate was centrifuged. The precipitate was washed three times with diethyl ether and then dried under reduced pressure to give the titled compound (621.4 mg, yield 98%). The structure was identified by 1H-NMR (CDCl3:CD3OD=1:1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:22]=1.[BH4-].[Na+]>O1CCCC1.CO>[NH2:17][C:13]1[CH:12]=[C:11]([CH:9]([OH:10])[CH2:8][N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:28]=3[CH:29]=[CH:30][C:21]([CH3:20])=[N:22]4)[CH2:32][CH2:33]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(N3CCN(CC(O)c4cccc(N)c4)CC3)cccc2n1
Reaction time: 1 h

Procedure:
Sodium carbonate (1.5 eq) and 2-bromo-1-(3-nitrophenyl)ethanone (1.5 eq) were added to a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq) in tetrahydrofuran at room temperature under an inert atmosphere, and the reaction was left under stirring for 1 h. The solution was then diluted with MeOH, NaBH4 (2 eq) was added and the reaction was left under stirring for 1 h. The solvent was removed under reduced pressure.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18])[CH2:2][CH:3]=C.O.I([O-])(=O)(=O)=[O:21].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[O:18]=[C:6]1[N:5]([CH2:1][CH2:2][CH:3]=[O:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCC=O)C(=O)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-but-3-enyl-3-oxopiperazine-1-carboxylate (0.246 mg, 0.97 mmol) in 10 mL of 1:1 acetone:water was added sodium metaperiodate (621 mg, 2.90 mmol), followed by a solution of 0.25 M aqueous osmium tetraoxide (0.192 mL, 0.048 mmol). After stirring overnight, the reaction was partitioned between EtOAc and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 257.3 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35])[CH3:30]>C(O)C>[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18](=[O:26])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:10]=2)=[O:5])[CH3:30]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
1-Cyano-7-(4-fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (70 mg, 0.2636 mmol) was dissolved/suspended in ethanol (4 mL) and 3-Amino-2,2-dimethyl-propionic acid ethyl ester (115 mg, 0.791 mmol) was added via syringe. The reaction was brought to reflux and maintained for 70 h. The reaction was cooled, concentrated and purified by medium pressure liquid chromatography (15 to 50% ethyl acetate in hexanes) to give the product as a white solid which was used immediately in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([C@@H:10]([CH2:17][CH2:18][CH3:19])[CH2:11][N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:25][CH3:26].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]([CH2:17][CH2:18][CH3:19])[CH2:11][N:12]2[CH2:15][CH:14]([O:16][CH2:25][CH3:26])[CH2:13]2)[CH3:9])=[O:7])=[CH:20][CH:21]=1
Reactant: CCI
Reactant: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC[C@@H](CN1CC(OCC)C1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To (S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide (Example 8.2 A) (85 mg, 0.27 mmol) in dry THF (3 mL) was NaH (60% in mineral oil) (16.41 mg, 0.41 mmol) added carefully. The mixture was stirred at rt for 30 minutes then iodoethane (0.023 mL, 0.29 mmol) was added in one portion. The mixture was left standing at rt on. NaHCO3 and DCM were added and the two layers were separated using a phase separator. The organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound (36 mg, 39%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.71, 0.86, 0.93-1.08, 1.08-1.32, 1.33-1.49, 2.36, 2.49-2.53, 2.54-2.61, 2.66, 2.70, 2.72-2.80, 3.19-3.32, 3.48, 3.96, 7.32, 7.38, 7.47. HRMS (M+H)+: calculated 339.1839. found 339.1840.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])=[C:5]([NH2:19])[NH:4][N:3]=1.[C:20](OC)(=[O:26])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])=[C:5]2[NH:19][C:20](=[O:26])[CH2:21][C:22](=[O:23])[N:4]2[N:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nn2c(c1Cc1cccc(C(F)(F)F)c1C)NC(=O)CC2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (2.0 g, 7.43 mmol), dimethyl propanedioate (1.03 g, 7.8 mmol) and in methanol (20 mL) stirred under nitrogen at 20° C. was added a solution of sodium methoxide (3.21 g, 14.9 mmol) in methanol (20 mL) dropwise during 15 minutes. The reaction mixture was stirred at 80° C. for overnight. After the reaction mixture was cooled to room temperature, precipitate was collected by filtration, then washed with methanol (5 mL×2). Product was dried under air. The product was then suspended with 1 N HCl (10 mL), stirred for 10 minutes, and filtered off HCl solution. The product was dried and used in next step without further purification. (2.41 g, 96%); LC/MS: MS (ES+) m/e 338 (MH+).