Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:17][OH:18])=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:6][CH:7]=1.[C:26](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C@@H:16]([N:15]2[C:3]3=[N:4][C:5]([NH:8][C:9]4[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=4)=[CH:6][CH:7]=[C:2]3[N:1]=[CH:26]2)[CH2:17][OH:18])=[CH:24][CH:23]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2ccc(N)c(N[C@@H](CO)c3ccc(F)cc3)n2)n[nH]1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(Nc2ccc3ncn([C@@H](CO)c4ccc(F)cc4)c3n2)n[nH]1

Procedure:
(R)-2-(3-Amino-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 62, 0.28 g, 0.82 mmol) and formamidine acetate (0.17 g, 1.6 mmol) in EtOH (5 ml) was heated at reflux overnight. Saturated sodium bicarbonate solution (10 ml) and EtOAc (30 ml) was added. The organic layer was separated, washed with brine (10 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (EtOAc-MeOH=40:1) to give the title compound as off white solid (0.021 g, 73%). 1H NMR (400 MHz) δ 11.72 (s, 1H), 9.24 (s, 1H), 8.33 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.40 (m, 2H), 7.17 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.27 (s, 1H), 5.71 (br s, 1H), 5.32 (t, J=4.2 Hz, 1H), 4.34 (m, 1H), 4.12 (m, 1H), 4.03 (m, 1H), 2.22 (s, 3H). MS: Calcd.: 352. Found: [M+H]+ 353.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([S:17]([NH:3][CH2:1][CH3:2])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CCN
Reactant: Nc1ncc(-c2cccc(S(=O)(=O)Cl)c2)cc1-c1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)c1

Procedure:
Ethylamine (2M in methanol, 0.117 ml) was added in one portion to a solution of 3-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]benzenesulphonyl chloride (0.045 g) and N-ethyl-N-isopropylpropan-2-amine (0.030 ml) in THF (2 ml) at ambient temperature, and the resultant mixture stirred for 20 hours. The mixture was then evaporated to dryness in vacuo and redissolved in NMP (2 ml), filtered and purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-N-ethyl-benzenesulphonamide (0.007 mg); Mass Spectrum: M+H+ 395.13; RT 2.59 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(N[C@@H]1CCCc2ccccc21)C(F)(F)F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
To a solution of (R)-2,2,2-trifluoro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (1 g) in acetone (30 mL) at 0° C. was added a solution of MgSO4.7H2O (2.0 g) in water (15 mL). After 5 min of stirring, KMnO4 (2 g) was added in small portions over 1 hr. The mixture was then stirred overnight, slowly warming to room temp. Celite was added and the mixture was filtered. The filtrate was treated with saturated sodium metabisulfite and filtered. The filtrate was extracted with DCM several times. The combined organic extracts were washed with distilled water and brine, dried over MgSO4 and concentrated in vacuo to afford 0.96 g (91%) of the title compound, whose purity was good enough to use crude. 1H-NMR (300 MHz, CDCl3) □ 8.2 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.5 (d, 1H), 6.8 (broad s, 1H), 5.5 (m, 1H), 2.9 (m, 2H), 2.6 (m 1H), 2.4 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])[CH:7]=[CH:8][CH:9]=1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:14]=[C:12]([CH:11]=[CH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:16])[F:1])[CH:5]=2)[O:13][CH:20]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1cccc(OC(F)(F)F)c1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1cccc(C=Cc2nc(CCl)co2)c1
Yield: 58.6 %

Procedure:
3-(3-Trifluoromethoxy-phenyl)-acrylamide (0.99 g, 4.27 mmol), dichloro acetone (1.90 g, 14.95 mmol) and toluene (8 ml) were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 2:1) yielding 0.76 g (71%) 4-chloromethyl-2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(C)cc3)CCC2)cc1
Yield: 92 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 260 mg (1.9 mmol) of 4-methylphenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 240 mg (92%) of 1-[2-(4-methylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 64.5°-66.5° C.; NMR (CDCl3) d 2.03 (m, J=7 Hz, 2H), 2.30 (s, 3H), 2.45 (s, 3H), 2.86 (t, J=7 Hz, 4H), 6.99-7.15 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([CH3:17])[C:10]=1[C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:27][C:28]([CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]2)=[CH:29][N:30]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:38][CH:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:28]3[S:27][C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[N:30][CH:29]=3)[CH2:33][CH2:34]2)=[O:15])=[C:11]([CH3:17])[C:10]=1[C:18]#[N:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)O)sc(NC(=O)OC(C)(C)C)c1C#N
Reactant: OCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)OCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)sc(NC(=O)OC(C)(C)C)c1C#N
Temperature: 60 °C
Yield: 25 %

Procedure:
The compound prepared in Example 222 (0.100 g), the compound prepared in Example 220 (0.123 g), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.102 g), N,N-diisopropylethylamine (0.185 mL) and 4-dimethylaminopyridine (0.011 g) were suspended in N,N-dimethylacetamide (10 mL) and heated at 60° C. overnight. The reaction mixture was cooled to room temperature and suspended between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 25 to 50% ethyl acetate/hexane/1% (9:1 methanol/concentrated ammonium hydroxide) to furnish the title compound (0.049 g) with the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:11].[CH2:12](O)[CH:13](O)[CH2:14]O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+]>CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[C:4]2[C:3]=1[N:11]=[CH:14][CH:13]=[CH:12]2
Reactant: OCC(O)CO
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: CS(=O)(=O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: CC(C)c1cc(Br)c2ncccc2c1
Temperature: 135 °C
Yield: 65 %

Procedure:
A mixture of 2-bromo-4-isopropyl-phenylamine (1.72 g, 8.0 mmol), propane-1,2,3-triol (1.84 g, 2.5 equiv), FeSO4 (0.067 g, 0.30 equiv), 3-nitrobenzenesulfonic acid sodium salt (1.13 g, 0.63 equiv) in 4.5 mL of methanesulfonic acid was heated to 135° C. for 3 hours and then cooled down to room temperature. 2 N Aqueous NaOH (˜40 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The organic layer was washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography using 5% to 20% EtOAc in hexane to afford the title compound (1.3 g, 65%) as dark brown solid. MS (ES) m/z 250.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4](I)([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:5].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C(OCC)(=O)C>[F:17][C:2]([F:1])([F:16])/[CH:3]=[C:4](/[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:8])\[CH3:5]
Reactant: CC(I)(CC(F)(F)F)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C/C(=C\C(F)(F)F)S(=O)(=O)c1ccccc1
Temperature: 70 °C
Yield: 72 %

Procedure:
To a solution of 14.0 mmol rac-(4,4,4-trifluoro-2-iodo-butane-2-sulfonyl)-benzene in 25 ml tetrahydrofuran and 2.5 ml water were added 42.1 mmol triethylamine and 42.1 mmol potassium carbonate. The mixture was heated at 70° C. for 6 h. The reaction mixture was then diluted with ethyl acetate and was washed sequentially with 1 N hydrochloric acid and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow oil (yield 72%). EI-MS (m/e): 250.1 (M+, 15%), 186.1 ([M−SO2]+, 38%), 125.0 (PhSO+, 100%), 77.1 (Ph+, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 800 mg, 4.1 mmol) in DMF (40 mL) was added glycine ethyl ester hydrochloride (625 mg, 4.5 mmol), HOBt (0.55 g, 4.1 mmol) and DIPEA (2.13 mL, 12.2 mmol). After 5 min, EDCI (1.01 g, 5.3 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (100 mL) and ethyl acetate (3×80 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (4:96) to give the title compound as a yellow solid. δH (CD3OD): 1.28 (3H, t), 4.14 (2H, s), 4.23 (2H, q), 7.10 (1H, s), 7.68 (1H, s), 8.59 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:26]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:35]([C:32]2[CH:33]=[CH:34][C:26]3[O:25][CH2:30][CH2:29][O:28][C:27]=3[CH:31]=2)=[O:36])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccc4c(c3)OCCO4)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid (29%). MS 494 (MH+).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][N:9]1[CH2:22][CH2:21][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1>O>[F:36][C:33]([F:34])([F:35])[C:30]1[N:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][N:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]3[CH2:10][N:9]([CH3:8])[CH2:22][CH2:21][C:12]2=3)=[CH:28][CH:29]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: FC(F)(F)c1ccc(CCCBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a suspension of DMF (5 mL) and sodium hydride (0.024 g, 0.0006 mol) at 0° c., 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) was added and stirred for 2 h at room temperature, Reaction mix was cooled to −20° c. and 5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.2 g, 0.00075 mol) was added, stirred for 1 h at 15° C. After completion (TLC), reaction mass was cooled to 0° c. and water (10 mL) was added, and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (3-4% methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide desired compound as brown oil (0.04 g, 20% yield). 2,8-Dimethyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.04 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.0000952 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.030 g, 61% yield).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:46]1([CH2:52][CH2:53][O:54][NH2:55])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.ClCCl>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:35]2[N:36]=[C:37]([Cl:44])[N:38]=[C:39]([NH:55][O:54][CH2:53][CH2:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]=2[N:41]=[CH:42]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NOCCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(NOCCc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 65.6 %

Procedure:
9-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), O-(2-phenylethyl)hydroxylamine hydrochloride (0.70 g, 4.0 mmol) and diisopropylethylamine (0.95 g, 7.4 mmol) were dissolved in 1,4-dioxan (40 ml) and heated at reflux for 3 days. After cooling the reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2×30 ml). The organic phase was dried (MgSO4). Flash chromatography on a silica gel column, eluting with heptane/ethyl acetate (1/1) gave the desired product as a foam (1.54 g, 66%), 1H NMR (DMSO-d6)γ 3.05 (2H, t, --OCH2 --), 4.19 (2H, t,--CH2Ph), 4.70 (1H, dd, H-5'a), 4.80 (1H, dd, H-5'b), 4.90 (1H, dd, H-4'), 5.22 (1H, t, H-3'), 6.39 (1H, t, H-2'), 6.59 (1H, d, H-1'), 8.51 (1H, s H-8).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(OCC)(=O)C.O>CN(C)C(=O)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][C:27](=[O:30])[CH2:28][CH3:29])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (500 mg, 1.3 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and propionyl chloride (370 mg, 4.0 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 16 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:20, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (224 mg, 53%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([C:4]2[C:5]3[O:12][C:9]4([CH2:11][CH2:10]4)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=2)[CH2:17][CH2:18]1
Reactant: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 42, 0.74 g, 2.4 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (8 mL), anhydrous tetrahydrofuiran, copper(I)iodide (0.050 g, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.22 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.62 g, 80%).
Reaction SMILES: N#N.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].[Li]CCCC.CON(C)[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20]>C1COCC1>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([C:19](=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=2[F:10])[CH2:22]1)=[O:28])([CH3:33])([CH3:32])[CH3:31].[F:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][C:9]=1[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccccc1F
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2F)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Under protection of N2, 1,2-difluorobenzene (22 g, 0.19 mol) in anhydrous THF (300 mL) was cooled to −78° C. and 2.5 M n-BuLi solution in hexanes (76 mL, 0.19 mol) was added dropwise slowly. The reaction mixture was stirred at −78° C. for 1 hr, the solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (47.7 g, 0.175 mol) in anhydrous THF (200 mL) was slowly added dropwise. The reaction mixture warmed to rt and stirred for 2 hrs. The mixture was quenched with saturated NH4Cl (300 mL), extracted three times with ethyl acetate, and dried over Na2SO4. Solvent removal and flash column chromatography afforded crude (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (40 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 7.51 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 4.19 (d, 1H), 3.96 (m, 1H), 3.23 (m, 1H), 3.04 (t, 1H), 2.85 (m, 1H), 2.06 (m, 1H), 1.75 (m, 1H), 1.62 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O.[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][NH2:20].O.N1C=CC(=O)N=1>C(O)(=O)C>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]1[C:4](=[O:14])[CH2:5][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:20]1
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C1C=CN=N1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1CC(F)(F)F

Procedure:
0.75 Mole (144 g) of benzoylacetic acid ethyl ester and 0.75 mole (126 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred for 3 hours in 900 ml of boiling acetic acid. The reaction mixture was poured out on 9 l of water. After 1 hour of stirring at room temperature the pyrazolone derivative was filtered and recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([O:25]CC)=[O:24])=[N:5][CH:4]=1.O.Cl>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([OH:25])=[O:24])=[N:5][CH:4]=1
Reactant: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCc3c(C(=O)O)ncc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (15.2 g) in THF (150 mL) was added LiOH monohydrate (5.16 g) and sufficient water to dissolve the solids. The reaction was allowed to stir at room temperature for 1.5 hours. The reaction was neutralized with 125 mL of 1N HCl and the THF was removed in vacuo. The resulting slurry was partitioned between CHCl3 and 10% aqueous KHSO4. The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness to afford the desired product as a pale tan foam. LRMS (M+1)=343.0
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>ClCCl>[C:13]([Si:17]([CH3:20])([CH3:19])[O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 881.2 %

Procedure:
Step A A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (10 g, 96 mmol) and imidazole (9.8 g, 140 mmol) in dichloromethane (200 mL) was added tert-butyldimethylchlorosilane (15.9 g, 10.6 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol as a colorless oil (20.4 g, 97%).