Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.FC1C=C(OC)C=C(F)C=1CN1[C:39]2[N:40]=[CH:41][CH:42]=[CH:43][C:38]=2[S:37](=[O:45])(=[O:44])[N:36]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=2)[C:35]1=[O:56]>>[F:1][C:2]1[C:3]([CH2:9][N:10]2[C:39]3[N:40]=[CH:41][CH:42]=[CH:43][C:38]=3[S:37](=[O:45])(=[O:44])[N:36]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=3)[C:35]2=[O:56])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: NCc1ncc(F)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3ncc(F)cc3F)c3ncccc3S2(=O)=O)cc1OC

Procedure:
The title compound (16 mg, 0.03 mmol) was prepared in two steps from (IntC1) (82 mg, 0.25 mmol) and (3,5-difluoropyridin-2-yl)methanamine (108 mg, 0.75 mmol); followed by 1,1′-carbonyldiimidazole (65 mg, 0.4 mmol) and triethylamine (28 uL, 0.2 mmol) using the methods of (95).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>N1C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:18])[N:4]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:5](=[O:17])[N:6]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CCCCCCNC(=O)n1cc(Br)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(Br)c(=O)n(C(=O)OCC(C)C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 132.8 %

Procedure:
5-Bromo-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide (Example 5) (0.06 g, 0.18 mmol) was dissolved in dry pyridine (1.5 mL), and isobutyl chloroformate (0.03 mL, 0.21 mmol) was added at 0° C. The reaction was stirred at room temperature for 15 hrs, and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 85:15) to afford the title compound (0.10 g, 48%) as a clear, colorless oil. 1H, NMR (400 MHz, CDCl3): δ 0.89 (t, J=6.8 Hz, 3H), 1.01 (d, J=6.7 Hz, 6H), 1.28-1.38 (m, 6H), 1.57-1.64 (m, 2H), 2.11 (h, J=6.7 Hz, 1H), 3.39 (td, J=7.1, 5.7, 2H), 4.25 (d, J=6.6, 2H), 8.74 (s, 1H), 8.80 (t, J=4.6 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.12, 18.90, 22.63, 26.58, 27.81, 29.18, 31.47, 41.76, 76.84, 98.78, 137.72, 148.46, 148.55, 149.44, 156.04. MS (ESI) m/z: 289 [M-CONH(CH2)5CH3]−.
Reaction SMILES: [CH:1]([C:5]1[C:6](O)=[C:7]([CH:10]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:12]=1)C=O)([CH2:3][CH3:4])[CH3:2].C(C1C(O)=C(C=C(/C=C/C(=O)C2C=CC(C)=CC=2)C=1)C=O)(CC)C.[C:49]([O:56][CH3:57])(=[O:55])[CH2:50][C:51]([O:53][CH3:54])=[O:52].CN1CCOCC1>CO>[CH:1]([C:5]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:10]=[C:7]2[C:54]=1[O:53][C:51](=[O:52])[C:50]([C:49]([O:56][CH3:57])=[O:55])=[CH:6]2)([CH2:3][CH3:4])[CH3:2]
Reactant: COC(=O)CC(=O)OC
Reactant: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C=O)c1O
Agent: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Solvent: CN1CCOCC1
Solvent: CO
Product: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc2cc(C(=O)OC)c(=O)oc12

Procedure:
A solution of 3-sec-butyl-5-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-hydroxybenzaldehyde of formula III (0.5 g, 1.46 mmol), dimethyl malonate (0.19 g, 1.46 mmol) in methanol (30 mL) was treated with N-methyl morpholine (0.3 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (25 mL) was added and extracted 3-fold with 25 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane. Concentration provides methyl 8-sec-butyl-6-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (General Formula IV). (0.49 g, 80% yield). White solid, m. p. 145-146° C.; 1H NMR (CDCl3, 300 MHz); δ 8.59 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.84-7.75 (m, 3H), 7.58-7.47 (m, 3H), 4.0 (s, 3H), 3.45-3.36 (m, 1H), 1.78-1.69 (m, 2H), 1.32 (d, 3H, J=7.0 Hz), 0.89 (t, 3H, J=7.3 Hz): 13C NMR (CDCl3, 75 MHz); δ 188.6, 163.4, 156.1, 154.0, 149.1, 143.1, 139.5, 136.7, 136.2, 131.6, 131.4, 130.0, 129.0, 127.3, 122.3, 118.4, 118.2, 52.9, 33.5, 29.6, 20.4. 12.0; ESI-MS (m/z): 425 (M+H)+.
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)=C.OO.[OH:16]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>CO>[OH:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([OH:16])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: C=C(C)c1ccc(OCCO)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: OCCOc1ccc(O)cc1

Procedure:
To a mixture of 2.50 g 2-(4-(1-methylethenyl)phenoxy)ethanol, 10 ml methanol, and 1.1 equivalents 50% aqueous H2O2 were added 0.1 equivalent 98% H2SO4. The reaction mixture warmed itself to reflux which subsided in a few minutes. After addition of 0.2 equivalent Na2SO3, methanol was removed under reduced pressure. The residue was taken up in ether, dried over Na2SO4 and NaHCO3, and filtered. Removal of solvent left 4-(2-(hydroxyethoxy)phenol in quantitative yield.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>ClCCl>[CH2:21]([O:20][C:18]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 95 %

Procedure:
Triethylamine (8.1 mL, 58 mmol) was added to a solution of piperidine-4-carboxylic acid (5 g, 40 mmol) and benzyl chloroformate (7.9 g, 46 mmol) in dichloromethane (100 mL) in an ice-water bath. After being stirred overnight, the solution was washed with concentrated HCl and brine, dried over Na2SO4 and concentrated. Chromatography on silica gel gave the title compound (10 g) as an oil. MS (M+H) 264.2.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1.O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.COC(OC)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:16][O:17][C:19]([CH3:24])([CH3:20])[O:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ncc2ncn(CCC(CO)CO)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OCC(CCn2cnc3cnc(N)nc32)CO1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (240 mg, 1.0 mmol) in N,N-dimethylformamide (3 ml) were added p-toluenesulphonic acid monohydrate (210 mg,1.1 mmol) and 2,2-dimethoxypropane (0.62 ml, 5.0 mmol) and the solution was stirred for 30 minutes. Potassium carbonate (110 mg, 0.8 mmol) was added and the solution was stirred for a further 30 minutes. Water (10 ml) was added and the solution was extracted with chloroform (3×8 ml). The organic layers were combined, dried (magnesium sulphate) and the solvent removed. Trituration with toluene-ether afforded 2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a white crystalline solid (262 mg, 94%) which was recrystallised from ethyl acetate-hexane (216 mg, 78%), m.p. 118+-120°; λmax (MeOH) 221 (27,200), 244 (4,920), and 308 (7,130)nm; νmax (KBr) 3450, 3140, 1635, 1615, 1580, and 1435 cm-1 ; &H [(CD3)2SO] 1.26 (3H, s, CH3), 1.33 (3H, s, CH3), 1.58 (1H, m, 3'-H), 1.74 (2H, q, J 7.1Hz, 2'-H), 3.54 (2H, dd, J 11.8Hz and 8.5Hz, 2×Hax), 3.78 (2H, dd, J 11.8Hz and 4.4Hz, 2×Heq), 4.07 (2H, t, J 7.2Hz, 1'-H), 6.46 (2H, s, D2O exchangeable, 2-NH2), 8.09 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 56.09; H, 6.91; N, 24.88%. C13H19N5O2 requires C, 56.30; H, 6.91; N, 25.25%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[F:9][C:10]1[CH:11]=[C:12]([NH:17][CH:18]([C:20](O)=[O:21])[CH3:19])[CH:13]=[C:14]([F:16])[CH:15]=1>>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:20](=[O:21])[CH:18]([CH3:19])[NH:17][C:12]1[CH:13]=[C:14]([F:16])[CH:15]=[C:10]([F:9])[CH:11]=1
Reactant: COC(=O)[C@H](C)N
Reactant: CC(Nc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)C(C)Nc1cc(F)cc(F)c1

Procedure:
Following General Procedure E and using L-alanine methyl ester hydrochloride (Sigma) and N-(3,5-difluorophenyl)-D,L-alanine (from Example C above), the title compound was prepared as a solid (mp=93-95° C.). The reaction was monitored by tlc (Rf=0.4 in 3% methanol/methylene chloride) and purification of this compound was by flash chromatography with 3% methanol/methylene chloride.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C:29](=[O:41])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:44])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:47])[CH2:22][C:23]([CH3:46])([CH3:45])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([C:29]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=3)=[O:41])=[C:27]([CH:42]([CH3:43])[CH3:44])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:47])[CH2:22][C:23]([CH3:45])([CH3:46])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
97 μl (540 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 3.04 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 2.5 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 68 mg (140 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethoxy)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 26A) in 4 ml of tetrahydrofuran is then slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. To bring the reaction to completion, the reaction mixture is again cooled to 0° C., and a further 97 μl (540 μmol) of borane/N,N-diethylaniline complex are added. The mixture is then thawed slowly to room temperature and stirred at this temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) and subsequent chiral HPLC (method 2) gives the target compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH3:35][C:29]([O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:20][CH:19]=1)([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
4-[2-(2-Phenyloxazol-4-yl)ethoxy]phenol (3.7 g, 13.0 mmol) and cesium carbonate (4.71 g, 14.5 mmol) were suspended in anhydrous DMF (100 mL) and treated with dropwise addition of ethyl 2-bromoisobutyrate (2.54 g, 13.0 mmol, 1.93 mL). The reaction mixture was stirred at ambient temperature for 24 h and then partitioned between ether (200 mL) and 1.0 N HCl (200 mL). The organic layer was washed with water (100 mL), dried over MgSO4 and concentrated to a brown oil, which was purified by gradient column chromatography (200 mL SiO2, 100% hexanes to 20% EtOAc/hexanes) to provide 2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid, ethyl ester (2.54 g, 50%) as a colorless, viscous oil: Rf=0.5 in 20% EtOAc/hexanes; 1H NMR (250 MHz, CDCl3) δ 7.96-8.02 (m, 2H), 7.37-7.46 (m, 3H), 6.81 (s, 4H), 4.32 (q, 2H), 4.20 (t, 2H), 3.03 (t, 2H), 1.52 (s, 6H), 1.27 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.OC1C2N=NNC=2C=CC=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:11]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2c(cc1Cl)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(c1cc2c(cc1Cl)OCO2)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.5 %

Procedure:
To a mixture of 6-chloro-1,3-benzodioxole-5-carboxylic acid (0.49 g,2.44 mmol) and hydroxybenzotriazole (66 mg, 0.49 mmol) in acetonitrile (20 mL) were added morpholine (0.53 mL, 6.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.52 g, 2.7 mmol). The orange solution was stirred 72 h at room temperature, diluted with ethyl acetate and poured into water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as white solid (0.53 g, 80%), mp 155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[H-].[Na+].C1(=O)O[CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[CH3:1][C:2]1[N:3]([CH2:18][CH2:17][OH:16])[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cc(-c2ccccc2)[nH]n1
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
A solution of 497 mg (3.14 mmol) of 3-methyl-5-phenylpyrazole in 12.6 mL of DMF at 0° C. was treated with 138 mg (3.45 mmol, 60% in oil) of NaH. After stirring for 15 min, 1.38 g (15.7 mmol) of ethylene carbonate was added, and the reaction was warmed to 25° C. and stirred overnight. The reaction was diluted with H2O and the product was extracted with hexanes/EtOAc (1:1). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (1:3) as eluent to give 305 mg (48%) of title compound: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[CH2:16][CH2:17][N:18]3[CH2:24][CH:23]4[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[CH2:7]1)[CH2:13]2>>[Cl:3][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[CH2:16][CH2:17][N:18]3[CH2:24][CH:23]4[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[CH2:7]1)[CH2:13]2
Reactant: O=S(Cl)Cl
Reactant: OC12CC3CC(C1)C(CCN1CC4CCC(CC4)C1)C(C3)C2
Product: ClC12CC3CC(C1)C(CCN1CC4CCC(CC4)C1)C(C3)C2

Procedure:
Thionyl chloride 5 ml was added to 3-[2-(5-hydroxy-2-adamantyl) ethyl]-3-azabicyclo[3.2.2] nonane 59.5 mg obtained in example 2 and refluxed for 16 hours. Reaction mixture was concentrated in vacuo and saturated sodium bicarbonate was added to the residue to set to alkaline pH, then extracted with chloroform. The extract was dried by adding ahnydrous sodium sulfate. After removal of drying agent, the filtrate was concentrated in vacuo, and the residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: acetone=15:1) to obtain the product as a mixture of stereoisomer. (a mixture of stereoisomer 1:1 measured by gas chromatography)
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C.Cl>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:31])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CCOC(=O)CCN
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)CCNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c2c1OC
Temperature: 100 °C
Reaction time: 10 h
Yield: 70.1 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.50 g, 5.39 mmol), β-alanine ethyl ester hydrochloride (2.48 g, 16.1 mmol) and triethylamine (4.50 mL, 32.3 mmol) in anhydrous DMSO (30 mL) was stirred at 100° C. for 10 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and acidified with 1M HCl. The product was extracted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Trituration of the residue with MeOH (30 mL) gave 5-amino-1-cyclopropyl-7-[2-(ethoxycarbonyl)ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.54 g, 70%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:49][C@@H:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:20]=[C:19]([CH:18]=[C:14]([C:15]([NH:49][C@@H:50]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH2:52][CH2:51]3)=[O:17])[CH:13]=2)[C:21]([O:23][CH3:24])=[O:22])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1nc(-c2cc(C(=O)O)cc(C(=O)OC)c2)cnc1N
Reactant: N[C@H]1CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cc(C(=O)N[C@H]3CCc4ccccc43)cc(C(=O)OC)c2)cnc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A mixture containing 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-5-[(methyloxy)carbonyl]benzoic acid (0.34 g, 1.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.51 g, 1.6 mmol), (S)-(+)-1-aminoindan (0.17 g, 1.3 mmol), diisopropylethylamine (0.6 mL, 3.4 mmol) and DMF (70 mL) were stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted 3' with ethyl acetate and 3× with 5% aqueous lithium chloride, and dried over sodium sulfate. Filtration, concentration, and purification by reverse phase HPLC gave the product as a yellow solid (0.41 g, 90% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.09 (d, 1H), 8.91 (s, 1H), 8.83 (d, 1H), 8.75 (t, 1H), 8.70 (t, 1H), 8.45 (t, 1H), 7.73 (br, 2H), 7.28 (d, 2H), 7.24-7.17 (m, 2H), 5.64-5.58 (q, 1H), 3.91 (s, 3H), 3.04-3.00 (m, 1H), 3.00-2.87 (m, 1H), 2.83 (d, 3H), 2.53-2.51 (m, 1H), 2.06-1.96 (m, 1H). MS (EI) for C24H23N5O4: 446 (MH+).
Reaction SMILES: C([O-])(=O)C.[K+].[C:6]1([S:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]#[N:28])[CH:19]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:29]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[C:6]1([S:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]#[N:28])[C:19]=2[Br:29])(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: CCCCn1nc(C#N)cc1CCCS(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCn1nc(C#N)c(Br)c1CCCS(=O)(=O)c1ccccc1
Yield: 45.2 %

Procedure:
Potassium acetate (3.82 g, 38.9 mmol) was added to a solution of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile (8.60 g, 25.9 mmol) in 50 mL of acetic acid. The reaction mixture was stirred until all solids had dissolved, followed by dropwise addition of bromine (1.33 mL, 25.9 mmol) over 5 minutes. The resultant red solution was stirred for 5 hours and aqueous sodium thiosulfate was added to quench excess bromine. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 200 mL of water. The pH of the mixture was adjusted to 8-9 by slow addition of solid sodium carbonate followed by extraction with several portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an orange oil. Purification via flash column chromatography on silica gel (eluting with hexane:ethyl acetate in a gradient from 3:1 to 1:1) afforded 4.80 g of 5-(3-benzenesulfonylpropyl)-4-bromo-1-butyl-1H-pyrazole-3-carbonitrile as a colorless oil that crystallized upon standing.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.N.Cl>O.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: Cn1cc(C=CC(=O)O)cn1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
A mixture of 1-methylpyrazole-4-carboxaldehyde (made as in reference 15) (18.1 g), malonic acid (17.1 g), pyridine (15 ml) and piperidine (0.2 ml) was heated to 100° C. for 1 hour. After cooling, water was added, followed by aqueous ammonia to obtain a clear solution, which was acidified to pH5 with hydrochloric acid. The resulting solid was filtered off, washed with water and dried to obtain 3-(1-methylpyrazol-4-yl)acrylic acid (18.9 g). 1H-NMR (d6-DMSO) δ 3.83 (3H, s), 6.18 (1H, d), 7.44 (1H, d), 7.83 (1H, s), 8.07 (1H, s). (APCI) M+H=153. C7H8N2O2 requires 152.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CN3CCCCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 72.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (416 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (328 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (386 mg) was obtained.