Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[K+].N[C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: [Br-]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)[C@H](Br)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 51.9 %

Procedure:
Potassium bromide (24.49 g, 0.21 moles) was first dissolved in a 2.50 N aqueous solution of sulfuric acid (120 mL). To this stirring solution was then added D-phenylalanine (10.00 g, 60.54 mmoles). After the addition, the mixture was cooled down to 0° C. and sodium nitrite (6.27 g., 90.87 mmoles) was added in small portions during 30 minutes. A strong bubbling was observed. The reaction was kept at this temperature for 50 minutes, and it was then allowed to proceed at room temperature for another 60 minutes. The crude product was isolated using standard work up and the obtained residue was purified by flash chromatography (SiO2, 30% ethyl acetate-70% hexanes) to give 7.20 g (51.9% yield) of the title compound as a yellowish oil: 1H NMR (CDCl3, 300 MHz) □ 10.86 (br s, 1H), 7.31 (m, 5H), 4.48 (t, 1H), 3.51 (dd, 1H), 3.29 (dd, 1H); 13C NMR (CDCl3, 75 MHz) □175.29, 136.26, 129.10, 128.69, 127.42, 44.83, 40.62.
Reaction SMILES: [F:1][C@:2]12[CH:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:32])[C@:15]3([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1.[CH:35]([NH:37][C@H:38]([C:43](O)=[O:44])[CH2:39][CH2:40][S:41][CH3:42])=[O:36]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:32])[C@:15]3([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C:16](=[O:19])[CH2:17][S:18][C:43](=[O:44])[CH:38]([NH:37][CH:35]=[O:36])[CH2:39][CH2:40][S:41][CH3:42])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1
Reactant: CCCCC(=O)O[C@]1(C(=O)CS)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@@]21C
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CCCCC(=O)O[C@]1(C(=O)CSC(=O)C(CCSC)NC=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 16.2 %

Procedure:
The title compound (1.03 gm) was prepared from 9-fluoro-11 -hydroxy-16β-methyl-17-(1-oxopentyloxy)-pregna-1,4-diene-3,20-dione-21-thiol (4.80 gm) and N-formyl-L-methionine (6.15 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7](CCl)[C:6]=2[CH:13]=1.[CH3:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([NH:15][CH3:14])[C:6]=2[CH:13]=1
Reactant: CN
Reactant: ClCC1=CCOc2ccc(Cl)cc21
Product: CNC1=CCOc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
500 ml of 33% ethanolic methylamine are added dropwise with cooling by ice/water to 105 g of 6-chloro-4-chloromethyl-2H-1-benzopyrane. Reaction is continued for 8 hours at room temperature, the mixture concentrated by evaporation and the residue taken up in dichloromethane. This solution is washed with 500 ml each of 1N NaOH and water, dried over MgSO4 and concentrated by evaporation. Distillation of the residue yields the title product b.p.: 116-120/13.3 Pascal.
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH:56]4[CH2:58][CH2:57]4)[C:50]=3[C:49](=[O:59])[N:48]2[C:60]2[CH:61]=[C:62]([NH:70][CH3:71])[C:63]3[N:64]([C:66]([CH3:69])=[N:67][N:68]=3)[N:65]=2)=[CH:43][CH:42]=1>CCCCCCC.C(Cl)Cl.CCO>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH:56]4[CH2:57][CH2:58]4)[C:50]=3[C:49](=[O:59])[N:48]2[C:60]2[CH:61]=[C:62]([NH:70][CH3:71])[C:63]3[N:64]([C:66]([CH3:69])=[N:67][N:68]=3)[N:65]=2)=[CH:43][CH:42]=1
Reactant: CNc1cc(N2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)nn2c(C)nnc12
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CCCCCCC
Solvent: CCO
Solvent: ClCCl
Product: CNc1cc(N2C(=O)c3c(c(C)nn3C3CC3)[C@H]2c2ccc(Cl)cc2)nn2c(C)nnc12

Procedure:
The title compound (38 mg, 34% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: Gilson PLC 2020; column: Chiralpak ID 5 μm, 20×250 mm; mobile phase: heptane/CH2Cl2/EtOH 70:25:5; flow: 10 mL/min; detection UV: 275 nm) of the racemic mixture of 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-5-(3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 113).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 94.2 %

Procedure:
3.9 g (20 mmole) of 7-hydroxy-2-methylchromen-4-one, 4.4 ml (40 mmole) of 1-bromo-3-chloropropane and 6.1 g (40 mmole) of anhydrous potassium carbonate in 100 ml of acetone were mixed and refluxed under heating for 16 hours. The mixture was allowed to cool and the insoluble solid was separated by filtration. The filtrate was evaporated to dryness, and the residue obtained was suspended in ethyl ether, filtered, washed with ether and dried at vaccum to yield 4.76 g (85%) of the product, melting point 113°-115° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[C:8]([C:11]1[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=1)([OH:10])=[O:9]>C1COCC1>[C:8]([C:11]1[S:15][C:14]([CH:16]=[C:1]2[C:2](=[O:3])[CH2:4][O:5][C:6]2=[O:7])=[CH:13][CH:12]=1)([OH:10])=[O:9]
Reactant: O=C1COC(=O)C1
Reactant: O=Cc1ccc(C(=O)O)s1
Solvent: C1CCOC1
Product: O=C1COC(=O)C1=Cc1ccc(C(=O)O)s1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
As before, 0.571 gm of tetronic acid (FW=100, 5.7 mmole) was reacted with 2.2 equiv. or 1.96 gm of 5-carboxy-2-thiophenecarboxaldehyde with 6 mL of THF and 10.5 mL of conc. HC1 and applied heat. A greenish precipitate formed immediately. Stirring was continued for 10 minutes. Workup and recrystallization from methanol gave 0.91 gm (67%) of the product having a M. p. of approximately 255°-268° C. and a molecular formula of C10H6O5S: calculated %C 50.42; %H 2.54; found %c 50.22; %H 2.75.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)#[N:32].CCN(C(C)C)C(C)C>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cc3)c2)c2cncnc21

Procedure:
Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Preparation 38), and 4-cyanophenylacetic acid with DIPEA.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(4-nitrophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-nitrophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]2[N:11]([N:13]=[CH:14][CH:15]=2)[CH:12]=1)(=O)=O.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][N:27]1[CH:31]=[C:30]([C:7]2[CH:8]=[C:9]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OS(=O)(=O)C(F)(F)F)cn2nccc12
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(NC(=O)OC(C)(C)C)c3ccnn3c2)cn1
Temperature: 100 °C

Procedure:
4-[(tert-butoxycarbonyl)amino]pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate (20.0 mg, 0.052 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21.8 mg, 0.105 mmol), tris(dibenzylideneacetone)dipalladium (0) (4.8 mg, 5.2 μmol), potassium fluoride (10.1 mg, 0.173 mmol), and tri-tert-butylphosphonium tetrafluoroborate (3.0 mg, 10.0 μmol) were suspended in DMF. The mixture was sparged with argon for 10 minutes, then heated to 100° C. for 2 h. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford a yellow gum. The gum was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to afford tert-butyl [6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]carbamate. 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H); 7.89 (s, 2H); 7.76 (s, 1H); 7.66 (s, 1H); 6.73 (s, 1H); 6.47 (s, 1H); 3.94 (s, 3H), 1.56 (s, 9H). LRMS (ESI) calculated for C16H20N5O2 [M+H]+, 314.2; found 314.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[Br:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([Cl:19])=[C:16]([OH:18])[CH:17]=1.O>CN(C)C=O>[CH2:9]([O:18][C:16]1[CH:17]=[C:12]([Br:11])[C:13]([F:20])=[CH:14][C:15]=1[Cl:19])[CH:8]=[CH2:7]
Reactant: Oc1cc(Br)c(F)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(Br)c(F)cc1Cl
Reaction time: 1 h

Procedure:
96.5 g (0.7 mol) of potassium carbonate and 54.9 g (0.45 mol) of allylbromide were added to a solution of 78.7 g (0.35 mol) of 5-bromo-2-chloro-4-fluorophenol in 350 ml of dimethylformamide. The reaction mixture was subsequently stirred for 1 hour and stirred into 2.5 l of water. The mixture was then extracted with dichloromethane (three times). The combined organic phases were washed with water (three times) and saturated aqueous sodium chloride solution (once), dried over magnesium sulfate and finally concentrated. The crude product was purified by distillation. Bp.: 106° C. (0.8 mbar); Yield: 85 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)c(C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Yield: 85.5 %

Procedure:
Using the procedure described in Example 1 (Step 10), ethyl ester (47) (0.33 g, 0.69 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.26 g (85%) of compound (48) as an off-white foam. 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 3.77 (s, 3H), 3.92 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.61 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 7.00-7.07 (m, 3H), 7.12 (d, J=2.5 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.56 (s, 1H), 7.63 (d, J=15.9 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H). LCMS (APCI): m/z 441 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH2:19]([O:18][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1)[CH3:20]
Reactant: CCOC(=O)C(C)C
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)Cc1ccc(CC(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of diisopropylamine (13.11 mmol, 1.8 mL) in anhydrous tetrahydrofuran (40 mL) cooled to −78° C. under a nitrogen atmosphere was added 2.5M n-BuLi in hexanes (13.11 mmol, 5.24 mL). The resulting solution was allowed to stir at −78° C. for 20 minutes, warmed to room temperature for 10 minutes, then cooled back to −78° C. for 10 minutes. The mixture was added to a solution of ethyl isobutyrate (13.11 mmol, 1.76 mL) dissolved in anhydrous tetrahydrofuran (20 mL) cooled to −78° C. The resulting solution was allowed to stir at −78° C. for 1 h. (4-Bromomethyl-phenyl)-acetic acid (1 g, 4.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the solution dropwise. The solution was warmed to room temperature and was allowed to stir for 20 minutes. The reaction mixture was poured over a dilute HCl solution (1 N). The aqueous layer was isolated and extracted with diethyl ether (1×). The organic layers were combined, washed with 2N HCl (2×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to a crude oil. The oil was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 10% methanol/methylene chloride to give 3-(4-carboxymethyl-phenyl)-2,2-dimethyl-propionic acid ethyl ester as a white solid (0.97 g, 84%).
Reaction SMILES: [F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3](OCC)=[O:4].[NH2:19][NH2:20].Cl>C(O)C>[F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3]([NH:19][NH2:20])=[O:4]
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
As shown in step 3-ii in Scheme 3, compound 1009 (10.0 g, 39.80 mmol) was dissolved in ethanol (100 mL), hydrazine (7.65 g, 7.50 mL, 239 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. After pouring the mixture into 2N HCl solution, the aqueous mixture was washed twice with DCM and the pH was adjusted to 8 while bubbling nitrogen gas through the solution. The resulting aqueous solution was exhaustively extracted with DCM (10×) and the combined organics dried over MgSO4, filtered, and the volatiles removed under reduced pressure to provide 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide as a yellow solid (compound 1010, 91% yield). This compound that was used directly without further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccccc4)ncnc32)[C@]1(C)F
Yield: 95.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 8 ml) was added benzylamine (about 0.56 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.22 g) as a colorless solid. Yield: 97%; 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 8.13-7.96 (m, 3H), 7.59-7.57 (m, 1H), 7.49-7.28 (m, 7H), 6.57 (d, 1H, J=23.1 Hz), 6.24 (bs, 1H), 4.89-4.79 (m, 3H), 4.50-4.43 (m, 1H), 2.18 (s, 3H), 1.90 (d, 3H, J=2.1 Hz), 1.47 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 534 (85%), [M+Na]+ 556 (100%). IR cm−: 3385, 1751, 1720, 1619, 1528, 1476, 1369, 1274, 1062, 712; HPLC: 95%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34](=[O:35])[O:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]([CH3:1])=[N:3]2)=[CH:19][CH:18]=1)(=[O:32])=[O:31]
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Product: Cc1nn(-c2ccc(CCOC(=O)NS(=O)(=O)c3ccccc3Cl)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1 of Example 2) and 2-chlorobenzenesulfonyl isocyanate: 1H-NMR (CDCl3) δ 8.21 (1H, d, J=7.5 Hz), 7.55-7.20 (12H, m), 4.30 (2H, t, J=6.8 Hz), 2.91 (2H, t, J=6.8 Hz), 2.34 (3H, s), 2.28 (3H, s).
Reaction SMILES: [NH2:1][C@@:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:8]([OH:10])=[O:9].O1CCOCC1.Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>C(=O)(O)[O-].[Na+].O>[CH2:24]([O:23][C:21]([NH:1][C@@:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:8]([OH:10])=[O:9])=[O:22])[CH:25]=[CH2:26]
Reactant: N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reaction time: 8 h
Yield: 67.3 %

Procedure:
(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15.0 g, 73.9 mmol) was slowly dissolved in 250 mL of saturated sodium bicarbonate. After complete solution, dioxane (100 mL) and allyl chloroformate (15.7 mL, 147.8 mmol) were added at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (100 mL) and washed with three portions of ethyl acetate. The organic layer was extracted once with saturated sodium bicarbonate. The combined aqueous layers were acidified to pH 1 with 4N hydrochloric acid and extracted with two portions of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the title compound as an oil (13.4 g, 67% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[C:17]([CH3:23])=[N:18][C:19]([CH2:20][CH2:21][CH3:22])=[C:12]2[N:11]=1)[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[C:17]([CH3:23])=[N:18][C:19]([CH2:20][CH2:21][CH3:22])=[C:12]2[N:11]=1)[CH3:2]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
1.64 g (5.25 mmol) of 2-(2-ethoxyphenyl)-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one (example VI) are added in portions to 3.14 ml of chlorosulfonic acid while cooling with ice. The reaction mixture is stirred at room temperature for 16 hours, then diluted with dichloromethane and poured onto ice water. The organic phase is washed with water and dried over magnesium sulfate and the solvent is removed in vacuo. 2.15 g (99%) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzene-sulfonyl chloride are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=1[F:34]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]3[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]3=[O:17])[CH:7]=2)=[CH:29][C:28]=1[F:34]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCc1ccc(Br)cc1C1C(=O)CC(C)(C)CC1=O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1ccc(Oc2ccc(Cl)c(F)c2)cc1C1C(=O)CC(C)(C)CC1=O
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-bromo-2-ethylphenyl)-5,5-dimethylcyclohexane-1,3-dione (0.236 g, 0.73 mmol), cesium carbonate (0.477 g, 1.46 mmol), 4-chloro-3-fluorophenol (0.535 g, 3.65 mmol), copper (II) trifluoromethanesulfonate (0.012 g, 0.04 mmol) and powdered 3 Å molecular sieves (0.300 g) is added anhydrous toluene (4 ml). After purging with nitrogen the reaction mixture is heated at 170° C. for 1 hour under microwave irradiation, then allowed to cool to room temperature. After quenching with 2M aqueous hydrochloric acid the crude product is extracted into dichloromethane (×2) and the phases are separated. Organic solvents are removed in vacuo and the crude product is purified by preparative reverse-phase HPLC to afford 2-[5-(4-chloro-3-fluorophenoxy)-2-ethylphenyl]-5,5-dimethylcyclohexane-1,3-dione as a white solid.