Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(O[CH:13]=[C:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]([CH3:22])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C
Yield: 58 %

Procedure:
4-Fluorophenylhydrazine (15.5 g) and ethyl 2-ethoxymethyleneacetoacetate (22.9 g) synthesized according to the method described in J. Chem. Soc. Perkin trans. I, p. 1875, 1988 were stirred in ethanol (200 ml) at a refluxing temperature for 2 h. After the evaporation of the solvent, the residue was recrystallized from a mixed solvent of ethyl acetate-n-hexane to give ethyl 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (17.7 g), melting point: 48–49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(Cl)c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)c(Cl)c2)sc2cc(O)ccc12
Yield: 59.2 %

Procedure:
By the method described in Example 2, the product of Example 4 (0.61 g, 1.14 mmol), ethanethiol (0.42 mL, 5.77 mmol), and aluminum chloride (1.07 g, 8.03 mmol) were stirred in anhydrous CH2Cl2 (20 mL). After chromatography (silica gel, 5-10% MeOH in CH2Cl2) the remnant crystallized from MeOH/CH2Cl2 to give 343 mg (59%) of the title product as a yellow solid; 1H NMR d 1.33 (m, 2H), 1.44 (m, 4H), 2.37 (m, 4H), 2.48 (s, 1H), 2.60 (t, J=5.7 Hz, 2H), 4.06 (t, J=5.7 Hz, 2H), 6.83-6.93 (m, 4H), 7.12 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.25 (m, 2H), 7.33 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 9.82 (br s, 1H); 13C NMR (DMSO-d6) d 23.8, 25.4, 54.2, 57.0, 65.9, 107.1, 114.5, 115.3, 116.9, 119.9, 123.5, 124.8, 128.2, 129.4, 129.5, 130.6, 131.7, 132.0, 138.5, 139.3, 153.5, 155.6, 162.9, 192.3; HRMS (FAB) m/e calc'd. for C28H27ClNO4S (MH+): 508.1349, found: 508.1344.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]([OH:13])=O.O[N:15]1[C:36](=[O:37])[NH:35][C@H:34]2[C@@H:16]1[CH2:17][S:18][C@H:19]2[CH2:20][CH2:21][CH2:22][CH:23](N1C(=O)CCC1=O)[C:24](=[O:26])[OH:25]>CN(C=O)C>[CH3:8][NH:9][CH2:10][C:11]([CH:23]([CH2:22][CH2:21][CH2:20][C@H:19]1[C@@H:34]2[C@@H:16]([NH:15][C:36]([NH:35]2)=[O:37])[CH2:17][S:18]1)[C:24](=[O:25])[OH:26])=[O:13]
Reactant: CNCC(=O)O
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 85 °C
Yield: 83.2 %

Procedure:
DMF (8.0 ml) and triethylamine (0.61 ml, 4.35 mmol) were added to solids N-methyl glycine (182 mg, 2.05 mmol) and N-hydroxy-succinimidyl biotin (500 mg, 1.46 mmol). The mixture was heated for 1 hour in an oil bath at 85° C. during which time the solids dissolved producing a clear and colorless solution. The solvents were then evaporated. The yellow oil residue was acidified with glacial acetic acid, evaporated and chromatographed on a 27 mm column packed with 50 g silica, eluting with 30% MeOH/EtOAc 1% HOAc to give the product as a white solid (383 mg) in 66% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N:20]([CH3:30])[CH3:19])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cccc(N(C)C)c3)cccc2c1N
Yield: 85.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3-dimethylaminophenyl boronic acid (160 mg, 0.97 mmol) were reacted to afford the title compound (99 mg, 88.6% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.60 (br, 1H), 7.83 (m, 2H), 7.70 (t, J=7.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 6.98 (m, 1H), 6.82 (dd, J=8.3 Hz, J′=2.3 Hz, 1H), 3.46 (q, J=6.7 Hz, 2H), 2.99 (s, 6H), 1.67 (m, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=350 (M+H) HPLC 1.60 min.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.CCO>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: CN1CC=C(c2c(N)cncc2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC(c2c(N)cncc2F)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.2 %

Procedure:
Pd on C, wet, Degussa (25 mg, 0.1175 mmol) was added to a stirred solution of 5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridin-3-amine (61 mg, 0.2943 mmol) in EtOAc (5 mL)/EtOH (5 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 15 hours. A further portion of Pd on C, wet, Degussa (25 mg, 0.1175 mmol) was added and the reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 24 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give 5-fluoro-4-(1-methylpiperidin-4-yl)pyridin-3-amine as an off-white solid (58 mg, 95% Yield). MS (ES+) 210.1.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)[CH:2]=[CH2:3]>CO.[Pd]>[N:24]1([C:22]([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:12][CH2:11][CH:10]([N:8]4[CH2:9][C@@H:5]([O:4][CH2:1][CH2:2][CH3:3])[C@H:6]([NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=5)[CH2:7]4)[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)=[O:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C=CCO[C@@H]1CN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCCO[C@@H]1CN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of rel-N-{2-[((3R,4R)-4-(allyloxy)-1-{1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-yl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide in methanol (400 μL) was added and palladium (10%) on carbon (50 mg) was added and purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas overnight. The flask was purged with argon; the mixture was filtered, then purified by preparative HPLC to afford the title compound as a white solid. 1H-NMR (CDCl3) δ: 0.82 (t, J=7.8 Hz, 3H), 1.43-1.53 (m, 2H), 1.59-1.68 (m, 1H), 1.89-1.93 (m, 2H), 2.46-2.51 (m, 2H), 2.73 (t, J=11.4 Hz, 2H), 2.85-2.96 (m, 2H), 3.10-3.20 (m, 2H), 3.29-3.36 (m, 2H), 3.41-3.69 (m, 10H), 3.79 (b, 1H), 4.05 (d, J=4.5 Hz 2H), 4.29-4.33 (%, 1 μl), 6.79 (d, J=8.7 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.43-7.49 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 8.07 (s, 1H). MS m/z: 646 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:19])[O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16].N1C=CC=CC=1>ClCCl>[Cl:16][C:15]([Cl:18])([Cl:17])[CH2:14][O:13][C:12](=[O:19])[NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[O:11]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)C(=O)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)C(=O)OC2)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 6-aminoisobenzofuran-1(3H)-one 1 (Maybridge, 13.43 g, 90 mmol) in dichloromethane (DCM, 200 mL) at 0° C. was added 2,2,2-trichloroethyl carbonochloridate 1a (18.23 mL, 135 mmol) and pyridine (17.79 mL, 180 mmol). The reaction mixture was stirred at room temperature (RT, ca. 25° C.) for 1 h. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) showed the reaction was complete. The reaction mixture was filtered and washed with DCM (2×30 mL) to afford carbamate 2 as a white solid (17.03 g, 58%). LCMS: [M+1]=324.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH:3]1[CH2:8][CH:6]2[CH2:5][CH2:4]1.O.S(=O)(=O)(O)[OH:11]>CC(C)=O>[OH:11][CH:2]1[CH:7]([OH:1])[CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2
Reactant: C1CC2CC1C1OC21
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: OC1C2CCC(C2)C1O

Procedure:
Into a four-neck flask (200 ml) were fed 20.3 g (185 mmol) of 2,3-epoxynorbornane, 50 ml of water, 25 ml of acetone, and 50 μl of sulfuric acid, and the reaction mixture was refluxed at 40° C. for 6 hours. After complete reaction, an object compound was extracted with each 40 ml of diethylether five times, and the resultant extract was washed with saturated salt solution (braine), and was dried with sodium sulfate to obtain 2,3-dihydroxynorbornane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=C(OC)N=1.COC1[C:24]2[N:25]([C:31](=[O:42])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=2)C=CC=1C=O>>[OH:18][CH:9]([C:8]1[CH:7]=[CH:6][N:25]2[C:31](=[O:42])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[N:33]=[C:24]2[C:3]=1[O:2][CH3:1])[C:10]#[C:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Reactant: COc1c(C=O)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Product: COc1c(C(O)C#Cc2ccccc2)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 8-methoxy-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde was reacted to give the title compound (1.05 g, 100%) as a pale yellow gum. LCMS (Method A): RT=4.75 min, [M+H]+=426.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19])=[O:13])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:22]=1)=[O:19])=[O:13]
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Reaction time: 12 h
Yield: 80.5 %

Procedure:
A mixture of 3-(3-benzyloxybenzamido)4-methyl-N-(3-morpholinophenyl)benzamide (4.49 g), 10% palladium-on-carbon (0.5 g) and ethyl acetate was stirred under an atmosphere of hydrogen gas for 12 hours. The resultant mixture was filtered through diatomaceous earth and the separated solids were washed with warm DMF (200 ml). The combined filtrates were concentrated to a volume of about 20 ml and water (50 ml) was added. The resultant solid was dried under vacuum at 55° C. There was thus obtained the title compound as a solid (2.99 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 3.07 (t, 4H), 3.72 (t, 4H), 6.67 (m, 1H), 6.97 (m, 1H), 7.18 (t, 1H), 7.36 (m, 6H), 7.78 (m, 1H), 7.92 (s, 1H), 9.68 (s, 1H), 9.89 (s, H), 10.01 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]1([CH3:10])[CH3:9].[O:11]=C1CC(C)(C)CC(C)=C1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][O:8][C:4](=[O:11])[C:3]1([CH3:10])[CH3:9]
Reactant: CC1CCCC(=O)C1(C)C
Reactant: CC1=CC(=O)CC(C)(C)C1
Product: CC1CCCOC(=O)C1(C)C

Procedure:
It is further noted that trimethylcyclohexanone can be prepared by a hydrogenation reaction of isophorone, followed by a Baeyer-Villiger reaction with a peracid to obtain trimethylcaprolactone on a commercial basis.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][OH:18])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:30]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[O-]S([O-])(=O)=O.[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][CH3:30])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCC[C@H]1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1OC(=O)C(C)C
Temperature: 22 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
A round bottom flask was charged with (3S,6S,7R,8R)-3-(tert-butoxycarbonyl-amino)-8-(2-hydroxyethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (200 mg, 0.48 mmol), Proton Sponge™ (700 mg, 4.05 mmol), Na2SO4 in CH2Cl2 (10 mL) at 0° C. To the resulting suspension was added trimethyloxonium tetrafluoroborate (Me3OBF4, 320 mg, 2.16 mmol), and the suspension was warmed to room temperature (about 22° C.) and stirred for 5 h. The mixture was diluted with EtOAc, filtered, and the filtrate was washed successively with water and 1M NaHSO4. The organics were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the crude product via column chromatography (hexanes/EtOAc gradient) afforded the title compound (140 mg, 71%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 5.41-5.16 (m, J=0.9 Hz, 2H), 5.06 (t, J=9.9 Hz, 1H), 4.94-4.73 (m, 2H), 3.69-3.52 (m, 1H), 3.42-3.27 (m, 2H), 3.26 (s, J=0.9 Hz, 3H), 2.80-2.67 (m, 1H), 2.60 (dt, J=13.9, 7.0 Hz, 1H), 2.08-1.86 (m, 1H), 1.66-1.55 (m, 1H), 1.45 (s, 9H), 1.27 (d, J=6.3 Hz, 3H), 1.20 (d, J=7.0 Hz, 6H); ESIMS m/z 454 ([M+Na]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.COC1C=CC(P(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]2[C:65]=1[C:66](=[O:84])[C:67]([C:77]1[CH:82]=[CH:81][CH:80]=[C:79]([F:83])[CH:78]=1)=[C:68]([CH:74](O)[CH3:75])[O:69]2>C1COCC1.O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:74]([C:68]3[O:69][C:70]4[C:65]([C:66](=[O:84])[C:67]=3[C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([F:83])[CH:78]=3)=[C:64]([F:63])[CH:73]=[CH:72][CH:71]=4)[CH3:75])[N:15]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:9][CH2:10][O:11][CH2:12][CH2:13]4)=[C:2]([F:1])[CH:3]=3)[C:22]=12
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(N4CCOCC4)c(F)c3)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N3CCOCC3)c(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
This example is also described in Example 59 of WO 2012/151525. To a solution of 3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.254 mmol) in THF (2 ml), tris(4-methoxyphenyl)phosphine (0.134 g, 0.381 mmol) and diisopropylazodicarboxylate (0.07 ml, 0.381 mmol) is added and stirred at room temperature (RT) for 10 minutes. To this mixture (−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.077 g, 0.254 mmol) is added and stirred for 12 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid. MP: 242-245° C. Enantiomeric excess: 96.21% Mass: 599.1 (M++1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH3:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].Cl.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:9](=[O:10])[CH2:8][CH2:7][C:6](=[O:5])[CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CCC(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCC(=O)c1ccccc1
Reaction time: 0.54 h
Yield: 24.07 %

Procedure:
To a well stirred suspension of anhydrous aluminium chloride (27.0 g, 205.9 mmol) in 126 ml of benzene was added 4-oxopentanoylchloride (23.0 g, 171.6 mmol) drop-wise, over a period of 30-35 minutes at room temperature (25-30° C.). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10 ml) the precipitated solid was filtered and the filtrate evaporated on a rotary evaporator to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2×100 ml), brine (100 ml) and dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform as eluent to give 8.6 g (24.07%) of the title compound.
Reaction SMILES: [CH:1]1([CH:4]2[NH:9][C:8](=[O:10])[CH:7]([CH3:11])[NH:6][C:5]2=[O:12])C[CH2:2]1.Cl.NC(CC)C(N[C@H](C(OC)=O)C)=O>>[CH2:1]([CH:4]1[NH:9][C:8](=[O:10])[CH:7]([CH3:11])[NH:6][C:5]1=[O:12])[CH3:2]
Reactant: CC1NC(=O)C(C2CC2)NC1=O
Agent: CCC(N)C(=O)N[C@@H](C)C(=O)OC
Agent: Cl
Product: CCC1NC(=O)C(C)NC1=O

Procedure:
Following the procedure for the preparation of 3-cyclopropyl-6-methylpiperazine-2,5-dione but substituting methyl N-(2-aminobutanoyl)alaninate hydrochloride and making non-critical variations provided the title compound as a solid: 1H NMR (DMSO-d6) δ 0.81-0.86, 1.25-1.27, 1.64-1.76, 3.73-3.91, 7.37, 8.07-8.15.
Reaction SMILES: FC(F)(F)C(O)=O.O1CCCCC1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>C(Cl)Cl>[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[N:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3c(cnn3C3CCCCO3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3[nH]ncc3c2)CC1
Reaction time: 2 h
Yield: 76.5 %

Procedure:
Trifluoroacetic acid (5.0 ml) was added to a solution of benzyl 4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate (500 mg, 1.00 mmol) in methylene chloride (50 ml) at room temperature and stirred for 2 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=50/1) to obtain benzyl 4-[(1H-indazol-5-ylamino)sulfonyl]piperidine-1-carboxylate (317 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(Br)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1Cc2cc(Br)ccc2Sc2ccccc21
Reaction time: 1 h

Procedure:
50 g of 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-one are dispersed in 250 ml of ethanol, treated with 9.9 g of sodium borohydride and stirred for 1 hour. After the addition of water, the mixture is extracted with ether. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-ol of melting point 108°-110° C. 49.9 g of 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 250 ml of benzene and 18 g of finely powdered calcium chloride are saturated with hydrochloric acid gas at 15° C and then stirred for a further 3 hours at room temperature. The precipitate is filtered off and washed with benzene. The filtrate is concentrated under reduced pressure. There is obtained 2-bromo-10-chloro-10,11-dihydro-dibenzo[b,f]thiepin of melting point 122.5°-124° C.
Reaction SMILES: C1[O:11][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:2]1.COC1C=C(C=CC=1O)C#N>>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: N#Cc1ccc2c(c1)OCO2
Agent: COc1cc(C#N)ccc1O
Product: N#Cc1ccc(O)c(O)c1
Yield: 94 %

Procedure:
The preparation was carried out according to the process of Example 2a except that 3,4-(methylenedioxy)benzonitrile was used as the starting material instead of 3-methoxy-4-hydroxybenzonitrile to form the reaction mixture. 3,4-Dihydroxybenzonitrile was obtained as a pale brown solid with a yield of 94% and a purity of greater than 97% as indicated by HPLC analysis.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>C(Cl)Cl>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 314 (20 mg) and TEA (15 μL) in DCM was added ethanesulfonyl chloride (10 μL). After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous NaHCO3. The organic phase was separated and dried over anhydrous Na2SO4. Evaporation under reduced pressure gave Compound 461. LC/MS (+ESI) m/z 476.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[NH:18]C(=O)C>>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:4](=[O:6])[C:3]3[C:2]([NH:18][C:17]=2[CH:16]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Product: Nc1ccc2c(=O)c3ccc([N+](=O)[O-])cc3[nH]c2c1

Procedure:
The compound S3 (Y═NH) was prepared using 2-chloro-4-nitrobenzoic acid and 3′-aminoacetanilide in the same way as S3 (Y═O). 1H-NMR (DMSO-d6) δ 11.54 (s, 1H), 8.32 (d, J=8.8, 1H), 8.26 (d, J=2.0, 1H), 7.92 (d, J=8.8, 1H), 7.86 (d, J=2.0, 8.4, 1H), 6.60 (dd, J=2.0, 8.8, 1H), 6.43 (d, J=2.0, 1H), 6.36 (bs, 2H). ESI-MS m/z (M+H) calc'd: 256.1, found 256.1.