Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:4].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.C(O)C>[OH:4][C:3]1[C@H:5]2[C@H:6]([CH2:7][CH2:8][CH2:9]2)[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:38](=[O:39])[C:37]=1[C:32]1[NH:31][C:30]2[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=2[S:34](=[O:36])(=[O:35])[N:33]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)C1CCCC1NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3cccc(C(F)(F)F)c3)C1=O)N2
Temperature: 60 °C
Yield: 45.3 %

Procedure:
2-(3-Trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.046 g, 0.15 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.051 g, 0.15 mmol) was added followed by N-methylmorpholine (0.04 mL, 0.33 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.033 g, 0.16 mmol) was added and the mixture was stirred at 25° C. for 3 h. The solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4 mL) and a 21% w/w solution of sodium ethoxide in ethanol (0.3 mL, 0.8 mmol) was added, and the reaction mixture was heated to 60° C. for 2 h. Upon cooling to 25° C., the reaction mixture was acidified to pH 2-3 with 2.0 M aqueous hydrochloric acid solution, upon which the product precipitated while stirring. The solid was collected by vacuum filtration and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-95% in 9 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-N-{3-[4-hydroxy-2-oxo-1-(3-trifluoromethyl-benzyl)-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.04 g, 0.068 mmol, 46%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.64 (3H, m), 1.96-2.18 (3H, m), 3.04 (3H, s), 3.95 (1H, d, J=7.2 Hz), 4.62 (1H, d, J=16.4 Hz), 5.00 (1H, d, J=15.6 Hz), 7.50 (4H, q, J=2.4 Hz), 7.57 (4H, m), 7.68 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C24H23F3N4O6S2 584.10, found 585.0 [M+H+]. [α]D=−47.7083.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](COC)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:31]=[C:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1>>[CH3:1][O:2][CH2:31][C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: COC[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: COC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 88 %

Procedure:
The title compound II-ae was prepared in 88% yield from 3,3:17,17-bis(ethylendioxy)-6α-methoxymethylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.25 (3H, s), 3.24 (2H, m), 2.53-0.75 (21H, m), 1.11 (3H, s), 0.87 (3H, s).
Reaction SMILES: [CH:1]1([O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C)=O)[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[CH:1]1([O:8][C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH2:19][C:20]#[N:21])[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(OC2CCCCCC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OC2CCCCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cycloheptyloxy)picolinate following the method described in Example 6 gave 3-(6-(cycloheptyloxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.29 g, quant.).
Reaction SMILES: [F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=3[CH3:23])[NH2:19])[C:3]=12.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:39])([F:40])([F:36])([F:37])[F:38])[CH:34]=1)[C:29]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([N:15]2[C:3]3[N:4]([N:5]=[C:6]([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[F:1])[CH:13]=[CH:14]2)[CH:17]=1)=[O:30])#[N:25]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)c(F)c12

Procedure:
Analogously to the process described in Example 126, 60 mg (0.195 mmol) of the compound of Example 83A and 53 mg (0.195 mmol) of the compound of Example 23A gave 61 mg (55% of theory) of the title compound. The product obtained from the preparative HPLC purification was dissolved in a little methanol and passed through a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After concentration of the eluate, the residue was dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27]([NH2:28])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]2)[CH:18]=1)[CH3:12]>O=S(Cl)Cl.C(Cl)Cl>[CH2:11]([O:13][C:14](=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27]([NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]2)[CH:18]=1)[CH3:12]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of 4-chlorobenzoic acid (312 mg, 2.0 mmol) in SOCl2 (10 mL) was heated to reflux for 2 h. After removal of the solvent, the residue was dissolved into CH2Cl2 (5 mL) and was dropped into a solution of Example Z (315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C., was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4) and filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid ethyl ester (290 mg, 64%). 1H-NMR (CDCL3): 8.02 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.36 (t, J=8.4 Hz, 3H), 6.87 (s, 1H), 4.06 (q, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.40 (s, 9H), 1.12 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 454 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([O:6][C@@H:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)=[CH:33][CH:32]=3)[CH3:30])=[CH:20][CH:19]=2)[C:8]([O:10]CC[Si](C)(C)C)=[O:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)=[CH:33][CH:32]=3)[CH3:30])=[CH:22][CH:23]=2)[C:8]([OH:10])=[O:9])=[CH:43][CH:44]=1
Reactant: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(F)cc2)C(=O)OCC[Si](C)(C)C)cc1)c1ccc(-c2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(F)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
The target compound (1.16 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 7 using 2-trimethylsilylethyl (S)-2-(4-fluorophenoxy)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate (1.84 g) obtained from Reference example 18 and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (7.5 ml).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[N:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=3)[CH2:14][CH2:15]2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C2CCN(c3ccncc3)CC2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulphonyl chloride (0.076 g) was added dropwise to a stirred solution of the product from part (ii) above (0.152 g) in pyridine (5.0 ml) at 0°. The mixture was stirred at room temperature for 3 hours and then evaporated. The residue was dissolved in water and an excess of solid sodium bicarbonate was added. The solid was filtered off, washed with water, dried and crystallised from methanol/ethyl acetate to give the title compound, (0.065 g), m.p. 269°-271° (with decomp).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[Cl:39][C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH:48]=[O:49])=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:48]([OH:49])[C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[CH:50]=[CH:51][CH:52]=2)=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)c3cccc(Oc4ccc(Cl)cc4)c3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-((3-(4-Chlorophenoxy)phenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3-(4-chlorophenoxy)-benzaldehyde instead of benzophenone) as a pale yellow oil.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:9][CH:8]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To an N,N-dimethylformamide (50.0 mL) solution of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 30 minutes at room temperature. 2-Fluoro-5-methylpyridine (1.80 g, 16.2 mmol) was then added at 0° C., and stirred for 5 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.67 g, 59.3%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1ccc(Cl)nc1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(3-amino-6-chloro-pyridin-2-yl)-methanol (998 mg, 4.0 mmol) is taken up in DCM and combined with MnO2 (697 mg, 8.0 mmol). After 24 h another 2 eq. MnO2 are added and the mixture is stirred for further 24 h at RT. Then the reaction mixture is filtered through Celite®, the solvent is removed and 3-amino-6-chloro-pyridine-2-carbaldehyde (HPLC-MS: tRet.=1.88 min, MS(M+H)+=157; method AFEC) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[O:28][C:27](=O)[C:26]2[S:30][CH:31]=[CH:32][C:25]1=2)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[O:28][C:27](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[C:26]2[S:30][CH:31]=[CH:32][C:25]1=2)[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2sccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2sccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (91 mg, 0.6 mmol.) in THF (1 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1 M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 4-ethyl-4H-thieno[2,3-c]furan-6-one, (67 mg, 0.4 mmol) in THF (1.5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried to give the title compound as a yellow solid (68mg, 57%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[C:6]3([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1.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]>[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[C:6]5([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]5[C:4]=4[N:3]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: CC12COCCN1c1nc(Cl)ncc1N(CC(F)(F)F)C2=O
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC12COCCN1c1nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc1N(CC(F)(F)F)C2=O
Yield: 49.8 %

Procedure:
A mixture of 2-chloro-6a-methyl-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (292 mg, 0.868 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (446 mg, 1.48 mmol), saturated aqueous NaHCO3 (2 ml) and PdCl2(dppf) (56.7 mg, 0.069 mmol) in 1,4-dioxane (4 ml) was irradiated in microwave at 110° C. for 30 minutes The reaction mixture was diluted with THF and passed through 0.45 μM PTFE syringe filter (washed with small amount of THF). The filtrate was purified by preparative HPLC (eluting with a gradient of 25-50% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). The fractions containing the desired product were combined and were evaporated under reduced pressure. Then NaHCO3 aqueous solution was added (in order to adjust the pH to basic) and extracted with EtOAc (THF was added to dissolve the precipitate). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (206 mg, 0.432 mmol, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 0.37-0.45 (m, 2H) 0.59-0.69 (m, 2H) 1.37 (s, 3H) 2.51-2.60 (m, 1H) 3.22-3.33 (m, 1H) 3.55-3.73 (m, 2H) 3.98-4.11 (m, 2H) 4.15-4.24 (m, 1H) 4.80-4.94 (m, 1H) 4.94-5.11 (m, 1H) 6.43-6.50 (m, 1H) 7.46-7.54 (m, 2H) 8.15-8.23 (m, 2H) 8.47 (s, 1H) 8.56 (s, 1H). MS [M+H] found 477.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH3:28]>C(#N)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:33][CH2:32][CH2:31][CH2:30][O:29][CH2:27][CH3:28])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CCCOS(C)(=O)=O)Cc1c2ccccc2cc2ccccc12
Reactant: CCOCCCN
Solvent: CC#N
Product: CCOCCCNCCCN(CC)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
The mesylate 17 (584 mg, 1.57 mmol) and 3-ethoxypropylamine (649 mg, 6.30 mmol) were dissolved in acetonitrile (30 mL). The mixture was then stirred at 75° C. under a N2 atmosphere overnight. After the confirmation of the disappearance of the mesylate by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (25 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 19 as a light yellow oil. Yield 60%; Rf=0.35 (0.5:4:85.5 NH4OH:MeOH:CH2Cl2); 1H NMR (CDCl3) δ 8.43 (d, 2H), 8.29 (s, 1H), 7.89 (d, 2H), 7.40 (m, 4H), 4.38 (s, 2H), 3.35 (q, 2H), 3.25 (t, 2H), 2.62 (q, 2H), 2.44 (t, 2H), 2.27 (t, 2H), 2.23 (t, 2H), 1.54 (q, 2H), 1.41 (q, 2H), 1.14 (m, 6H); 13C NMR (CDCl3) δ 131.3, 131.2, 130.6, 128.9, 127.2, 125.4, 125.0, 124.7, 69.1, 66.0, 50.7, 50.6, 48.2, 47.5, 47.2, 30.1, 27.1, 15.4, 11.9.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:5]=1[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])([O-])=O>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:5]=1[C:6]([NH:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1N
Reaction time: 4 h
Yield: 99.3 %

Procedure:
A solution of 34B (710 mg, 2.37 mmol) in MeOH (8 mL) was treated with 20% palladium hydroxide on carbon (110 mg). The resulting slurry was stirred under a hydrogen atmosphere for 4 hours, and then filtered through a 0.4 μm polycarbonate membrane to remove the catalyst. The filtrate was concentrated to give 34C as a white solid (636 mg, 99%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.ClC1C=C([F:20])C=CC=1C=O.S1(CCCC1)(=O)=O.[F-].[K+]>>[F:10][C:4]1[CH:3]=[C:2]([F:20])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=Cc1ccc(F)cc1F

Procedure:
158.5 g (1 mol) of a mixture of 56% of 4-chloro-2-fluoro-benzaldehyde and 44% of 2-chloro-4-fluorobenzaldehyde were heated together with 700 g of sulfolane and 75 g (1.29 mol) of potassium fluoride at 215° C. for 10 h. The working up was carried out as in Example 1. 99.5 g of 2,4-difluorobenzaldehyde equivalent to 70% of the feed-stock was obtained.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH3:41])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:41][O:40][C:22]1[CH:21]=[C:20]([CH:39]=[CH:38][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:19][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (6.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (8.96 g), potassium carbonate (7.20 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 60° C. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylate (13.15 g, yield 95%). The crystals were recrystallized from acetone-hexane. melting point: 160-161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=C)[C:5]#[N:6].[O:12]=[O+][O-].[BH4-].[Na+].O>CO>[OH:12][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: C=Cc1ccc(C#N)cc1C
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)ccc1CO
Temperature: -70 °C
Yield: 90 %

Procedure:
3-Methyl-4-vinylbenzonitrile (0.40 g; 2.8 mmol; from step (i) above) was dissolved in 50 mL of methanol and cooled to −70° C. Ozone (2 eq.) was bubbled through, and then 0.20 g (5.3 mmol) of sodium borohydride and 5 mL of water were added and the cooling bath was removed. After 4 h the methanol was evaporated and the residue was partitioned between 1M HCl and ether. The aqueous layer was extracted twice with ether and the combined organic phase was washed with water, dried (Na2SO4) and evaporated to yield 0.37 g (90%) of the desired product, which was used in the next step without further purification.