Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]([C@@H:14]([NH:16][C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4C3CCCCO3)[CH3:15])=[CH:12][C:11]3[C:6](=[C:7]([CH3:32])[CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>Cl.CCO>[N:25]1[C:17]([NH:16][C@H:14]([C:13]2[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:33])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:32])[CH3:15])=[C:18]2[C:22]([NH:21][CH:20]=[N:19]2)=[N:23][CH:24]=1
Reactant: Cc1cccc2cc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(C3CC3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(C3CC3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
2-Cyclopropyl-8-methyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (compound 5004) (222 mg, 0.5 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with saturated NaHCO3 solution to pH=7-8, and then extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate and hexanes (1:1). The solid was collected by filtration and dried in vacuo to afford the desired product, (S)-3-(1-(9H-purin-6-ylamino)ethyl)-2-cyclopropyl-8-methylisoquinolin-1(2H)-one (5005, compound 200 in Table 4) (150 mg, 83% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH2:7]2.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:15][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH:11]([CH3:12])[CH3:13])[C:8](=[O:14])[CH2:7]2
Reactant: CC(C)N1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)N1C(=O)Cc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (0.854 g, 15.3 mmol) is added portionwise to a mixture of 7-fluoro-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (17, 0.91 g, 3.82 mmol) and ammonium chloride (2.04 g, 38.2 mmol) in ethanol (50 ml) and water (25 ml) at 90° C. The reaction is stirred vigorously and heated for 30 min, cooled to room temperature and diluted with dichloromethane (150 mL). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a solid. HPLC r.t. 2.97 min; MS for C11H13FN2O m/z 209.1 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[O:18]1CC[CH2:20][CH2:19]1.[BH4-].[Na+]>CO>[OH:18][CH:19]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)[CH3:20]
Reactant: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution containing 4-acetoxy-4'-hydroxy-1,1'-biphenyl from part A (5.0 g, 23.6 mmol) in methanol (500 mL) and tetrahydrofuran (30 mL) is treated with sodium borohydride (0.9 g, 23.8 mmol) in portions over 30 minutes at room temperature. After 2 hours, the reaction mixture is concentrated under reduced pressure, diluted with water (400 mL), acidified with 2N HCl and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over MgSO4 and concentrated to a solid residue. Crystallization of the solid from ethyl acetate gives 4.7 g (92.9%) of the title compound, m.p. 159°-160° C.; MS (EI m/z): 214 (M)+ and 199 (b.p. M--CH3)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1>O1CCCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][CH:16]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOc1ccc(Br)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 114.7 %

Procedure:
To a solution of NaH (0.160 g, 6.68 mmol) in anhydrous tetrahydrofuran (20 mL) was added diethyl malonate (1.07 g, 6.68 mmol) dropwise at 0° C. The resulting colorless solution was stirred at 0° C. for 15 minutes, then at room temperature for 30 minutes before cooling again to 0° C. A solution of 1-bromo-4-(2-bromoethoxy)benzene (1.70 g, 6.07 mmol) in anhydrous tetrahydrofuran (10 mL) was added over 5 minutes. The resulting mixture was heated at reflux until complete as judged by TLC. The mixture was cooled to room temperature and carefully quenched with water and then extracted with ethyl acetate (4×50 mL). The combined organic phases were dried over sodium sulfate filtered and concentrated under reduced pressure to give the title compound (2.5 g) as a colorless oil which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) ppm 7.43-7.32 (m, 2H), 6.84-6.68 (m, 2H), 4.32-4.14 (m, 4H), 4.01 (m, 2H), 3.64 (m, 1H), 2.43-2.32 (m, 2H), 1.33-1.18 (m, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:31])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:5]([C:4]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:3]=1[CH2:2][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:31])[CH:14]=1)#[N:6]
Reactant: N#Cc1cc(F)ccc1CBr
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)cc2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3C#N)cc2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 2-(bromomethyl)-5-fluorobenzonitrile (4.31 g, 20.1 mmol) and methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (5.00 g, 18.3 mmol) in DMF (20 mL) was added K2CO3 (3.00 g, 22.0 mmol). The reaction was allowed to warm to RT and stirred overnight. Additional 2-(bromomethyl)-5-fluorobenzonitrile (0.39 g, 1.83 mmol) and K2CO3 (0.25 g, 1.83 mmol) were added and the reaction heated at 60° C. for 2 h. Solvent removed by distillation. Reaction neutralized with 5% citric acid (50 mL). Organic products were extracted in DCM (3×25 mL), dried over Na2SO4, filtered, and concentrated to a thick dark brown oil. Purified by silica gel flash column chromatography using EtOAc as the eluent to give the product as a brown solid, dried in vacuo (6.18 g, 76%). 1H NMR (CD3OD/400 MHz) δ8.03 (m, 1H), 7.76 (m, 2H), 7.66 (m, 1H), 7.52 (m, 2H), 6.24 (s, 1H), 6.09 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 407.1408 (M+H calculated for C23H20FN2O4 requires 407.1402).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: ClCCN1CCOCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)morpholine
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:5]=[C:4]([CH2:3][C:1]#[N:2])[NH:14]2)=[CH:20][CH:21]=1
Reactant: N#CCC(N)=S
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc(=O)c2ccc(Cl)cc2[nH]1
Reaction time: 6 h
Yield: 18.5 %

Procedure:
2-cyanoethanethioamide (300 mg, 3.00 mmol) and bromoethane (299 μL, 4.00 mmol) were added to an ethanolic solution of sodium ethoxide (4.00 mmol, 3 mL). The resulting mixture was stirred for 6 hours, 2-amino-4-chlorobenzoic acid (500 mg, 2.91 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (118 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.19 (s, 2H), 7.57 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]#[N:16])[O:11][N:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH:18]S(O)(=O)=O>>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]([NH2:16])=[O:18])[O:11][N:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C(=O)c2noc(CC#N)n2)cc1
Product: Cc1ccc(C(=O)c2noc(CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 23 g of [3-(4-toluoyl)-1,2,4-oxadiazol-5-yl]acetonitrile and 200 ml of 98% H2SO4 was stirred at room temperature overnight. The resulting solution was added slowly to 3000 ml of ice water with mechanical stirring to precipitate a solid. The collected solid was washed with excess water and 600 ml of cold isopropanol, and dried in vacuo to give 21 g (86%) of a solid, m.p. 169°-171°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:63]=[N+:64]=[N-:65])(C)C.N([O-])=O.[Na+]>C(#N)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:65]=[N:64][N:63]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C(NCc1ccccc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1nnnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.50 g (S)-2-Benzylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester and 2.91 g triphenylphosphine in 30 ml acetonitrile were added dropwise at 0° C. 2.3 ml diisopropylazodicarboxylate and after 2 minutes 1.5 ml trimethylsilylazide over a period of 20 minutes. After 30 minutes the mixture was allowed to warm to RT and stirred for 12 h. The mixture was cooled to 0° C. and 1.5 ml aqueous sodium nitrite (2.9 M) were added, after 30 minutes a solution of 2.4 g ceric ammonium nitrate in 15 ml water was added and stirred for another 20 minutes. After this time the mixture was poured into ice and extracted twice with dichloromethane. The crude product thus obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 494 mg colorless foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:34][C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:25][CH:26]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(Cc5ccc(C(F)(F)F)cc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.4 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (25 mg, INTERMEDIATE 15) in tetrahydrofuran (5 ml) was added sodium hydride (5 mg of a 60% dispersion in oil). The reaction was allowed to stir at room temperature for five min, and then 1-(bromomethyl)-4-(trifluoromethyl)benzene was added. The reaction was stirred for 1 h and then was concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (5 mg, 14.4%). Mass spectrum (ESI) 561.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.5 Hz, 2H), 7.92-7.94 (m, 3H), 7.55 (d, J=8 Hz, 2H), 7.50 (s, 1H), 7.42 (d, J=8 Hz, 2H), 6.37 (m, 1H), 3.54 (s, 2H), 3.44-3.51 (m, 2H), 3.40 (m, 2H), 2.89 (m, 2H), 1.98-2.03 (m, 2H), 1.83 (s, 1H) 1.74-1.77 (m, 2H), 1.67-1.71 (m, 1H), 1.45 (d, J=7 Hz, 6H), 1.36-1.40 (m, 2H), 1.25 (m, 1H).
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH2:37]([CH:41]1[CH2:52][CH:51]=[CH:50][CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][CH:44]([CH2:53][CH:54]([CH3:56])[CH3:55])[N:43]=[N:42]1)[CH:38]([CH3:40])[CH3:39]>>[NH2:42][CH:41]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]([NH2:43])[CH2:53][CH:54]([CH3:56])[CH3:55])[CH2:37][CH:38]([CH3:39])[CH3:40]
Reactant: CC(C)CC1CC=CCCC=CCC(CC(C)C)N=N1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CC(C)CC(N)CCCCCCCCC(N)CC(C)C

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 400 g (1.45 mols) of 3,12-diisobutyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, as the main fraction, 261 g (63% of theory) of 4,13-diamino-2,15-dimethylhexadexane as colourless oil [b.p. 168°-172° C./0.4 Torr; nD20 =1.4561; IR (liquid) inter alia bands at 3289, 3205 and 1600 cm-1 ].
Reaction SMILES: C[Mg]Cl.C[C:5](C)([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)[CH:6]=[O:7].Cl.O1C[CH2:21][CH2:20][CH2:19]1>>[CH3:19][CH:20]([CH3:21])[CH:6]([OH:7])[CH2:5][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1
Reactant: Cc1cccc(CC(C)(C)C=O)c1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: Cl
Product: Cc1cccc(CCC(O)C(C)C)c1
Reaction time: 5 h

Procedure:
A solution of 10 g of methylmagnesium chloride in 100 ml of tetrahydrofuran was added at a temperature of from 25° C. to 30° C., and with the exclusion of air, to 17 g of 2,2-dimethyl-3-(3-methylphenyl)-propionaldehyde (according to Example 3). After 5 hours at 30° C., the reaction mixture was poured onto ice and acidified with hydrochloric acid. The phases were then separated and the organic phase was washed with 100 ml of water and 100 ml of sodium bicarbonate solution. Finally, drying was carried out with solid potassium carbonate. Fractional distillation yielded 15 g of end product at 0.12 mbar in a temperature range of from 79° C. to 82° C.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: COc1cccc2c1C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1C(O)=C(C(=O)NCC(=O)O)C(=O)C21CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A mixture of 1,1-dimethylethyl N-((4-hydroxy-5-(methyloxy)-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (32 mg, 77 μmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=362, M−1=360. The mixture was concentrated in vacuo, and purified by column chromatography eluting with 0.1:10:100 TFA/MeOH/DCM to give 9 mg of the product as a pale yellow solid. MS (m/z)=362 (M+H)+. Calculated for C18H19NO7 361.12.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Br[C:35]1[CH:46]=[CH:45][C:38]2[C:39](=[O:44])[NH:40][S:41](=[O:43])(=[O:42])[C:37]=2[CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:35]5[CH:46]=[CH:45][C:38]6[C:39](=[O:44])[NH:40][S:41](=[O:42])(=[O:43])[C:37]=6[CH:36]=5)[CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NS(=O)(=O)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1ccc2c(c1)S(=O)(=O)NC2=O
Temperature: 120 °C

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (46 mg, 0.10 mmol), 6-bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (26 mg, 0.10 mmol), Pd(dppf)Cl2 (4.0 mg, 0.0050 mmol), 2M Na2CO3 (150 μL, 0.30 mmol), and DMF (1 mL) were combined and heated at 120° C. in the microwave for 10 min. The mixture was filtered and purified by reverse phase preparatory HPLC to give 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-[4-methyl-3-(1,1,3-trioxo-2,3-dihydro-1λ6,2-benzothiazol-6-yl)phenyl]cyclopropane-1-carboxamide. ESI-MS m/z calc. 512.5, found 513.5 (M+1)+. Retention time 1.93 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:35]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:34]=4[O:33][CH3:32])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(OC)ccc4OC)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,5-dimethoxy-benzenesulfonyl chloride. Purity (ELSD, based on MW=621.7)=90%.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C>ClCCl>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH2:12][CH2:13][CH2:14][OH:15])=[CH:17][CH:18]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCCCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A suspension of aluminium trichloride (10.2 g, 76.5 mmol) in dichloromethane (250 ml) at 0° C. was added with the borane-tert-butylamine complex (13.2 g, 153 mmol) and the mixture was left under stirring at 0° C. for 15 minutes. After that the mixture was added with 3-(4-fluorobenzoyl)propionic acid (5 g, 25.5 mmol) stirring at room temperature for 20 h, then added slowly with 0.2M HCl (75 ml) and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with 0.2M HCl and with a NaCl saturated solution, dried and the solvents were removed under reduced pressure. The resulting residue was purified by chromatography through a silica gel column, eluting with hexane:ethyl acetate, 8:2, thereby recovering 2.70 g of the title product as a colourless oil (63% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][C:6]=2[Br:18].[CH2:20]([O:22][CH2:23][C:24](Cl)=O)[CH3:21].C(O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Br:18][C:6]1[C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:21]([CH2:20][O:22][CH2:23][CH3:24])[N:12]([CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3c(Br)cccc3c2n1CC(C)(C)O
Temperature: 40 °C
Reaction time: 36 h
Yield: 80.8 %

Procedure:
A solution of 1-(3-amino-8-bromo-2-chloroquinolin-4-ylamino)-2-methylpropan-2-ol (4.65 g, 14.4 mmol) and ethoxyacetyl chloride (1.9 mL, 15.8 mmol) in dichloromethane (72 mL) was stirred for one hour at ambient temperature. The solvent was removed under reduced pressure, and ethanol (43 mL), water (29 mL), and potassium carbonate (3.98 g, 28.8 mmol) were added. The reaction was stirred at 40° C. for 36 hours. The solvent was removed under reduce pressure, and the residue was diluted with water. The aqueous solution was extracted with chloroform, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 4.4 g of 1-(6-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as an orange solid.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([N:34]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Agent: Cl
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3cccc(Cl)c3)c2)cc1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 23, except for using 4,4,5,5,5-pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one prepared in Step 3 of Preparation 4; and using 3-chlorophenylhydrazine hydrochloride instead of 4-chlorophenylhydrazine hydrochloride.