Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[N:8]=[CH:7][C:6]=1/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21].CC1C=CC(S(NN)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[N:8]=[CH:7][C:6]=1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Temperature: 25 °C

Procedure:
A 25 mL round-bottomed flask is charged with (E)-methyl 3-(4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)acrylate (455 mg, 1.13 mmol), 4-methylbenzenesulfonohydrazide (1050 mg, 5.64 mmol), and toluene (10 mL). The reaction mixture is heated at reflux for 12 hours, then cooled to room temperature and concentrated in vacuo. The residue is purified by silica gel (20 to 30% EtOAc in hexanes) to afford methyl 3-(4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)propanoate.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[C:14]([C:19]4[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=4[O:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:36]([CH3:41])=[CH:37][C:38]([OH:40])=[O:39])(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O1CCOCC1>[CH2:32]([O:31][C:20]1[C:21]([CH:28]([CH3:30])[CH3:29])=[CH:22][C:23]([CH:25]([CH3:26])[CH3:27])=[CH:24][C:19]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([C:36]([CH3:41])=[CH:37][C:38]([OH:40])=[O:39])[NH:10]2)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)O)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCOc1c(-c2cccc3[nH]c(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 103 %

Procedure:
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-but-2-enoic acid (32 mg, 0.056 mmol) was dissolved in ethanol (1 mL)/dioxane (1 mL) and treated with 2.5N KOH (1 mL, 1 mmol) at 70-75° C. for 24 h. The reaction was neutralized with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic portions were washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 25 mg of a residue. The material was purified using radial chromatography with a gradient of hexane/ethyl acetate to provide 13 mg (53%) of a yellow amorphous foam. 1H NMR (250 MHz, CDCl3): δ 8.26 (bs, 1H), 7.26-7.15 (m, 3H), 7.06 (m, 2H), 6.83 (s, 1H), 6.11 (s, 1H), 3.37 (m, 1H), 3.22 (t, 2H, J=6.3), 2.86 (m, 1H), 2.55 (s, 3H), 1.23 (m, 14H), 0.95 (m, 2H), 0.54 (t, 3H, J=7.2). MS [EI+] 434, (M+H)+, [EI−] 432 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[C:5]([O:8][C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]2)=[N:6][CH:7]=1>[Fe].C(O)(=O)C>[NH2:19][C:4]1[C:5]([O:8][C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)C1(Oc2ncc(Cl)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1(Oc2ncc(Cl)cc2N)CC1
Reaction time: 7 h
Yield: 90.6 %

Procedure:
At room temperature, to an acetic acid solution (100 ml) of tert-butyl 1-[(5-chloro-3-nitropyridin-2-yl)oxy]cyclopropanecarboxylate (9.61 g) was added iron powder (13.6 g), and stirred for 7 hours, followed by concentration under reduced pressure. To the residue were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution for neutralization, followed by filtration through Celite. The organic layer separated from the filtrate was washed with saturated sodium chloride solution, and the aqueous layer was collected and extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 1-[(3-amino-5-chloropyridin-2-yl)oxy]cyclopropanecarboxylate (7.88 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (64 mg, 77%), MS (ISP) m/z=334.6 [(M+H)+], mp 261° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>>[C:24]1(=[O:33])[N:23]([CH2:22][CH2:21][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[N:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C@@H:6]3[CH2:1]2)[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: c1ccc2c(c1)Cc1cccnc1N1CCNC[C@@H]21
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ncccc3Cc3ccccc3[C@@H]2C1
Yield: 47 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-1,2,3,4,10,14b-hexahydropyrazino [2,1-a]pyrido[2,3-c][2]benzoazepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 47%.
Reaction SMILES: [C:1]([O:6][CH:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].CCCCCC>CC(OC)(C)C.O>[C:1]([O:6][C@@H:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OC(OC(C)=S)C(C)C
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CCCC(=O)O[C@@H](OC(C)=S)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
2-Methyl-1-methylthiocarbonyloxypropyl butanoate (2d) (1 g) was dissolved in 20 mL of MTBE, saturated with 1% of water, 1.3 g of PLE/MPEG (7.5% , 60 mg/1 g) was added, and the mixture shaken at room temperature for 24 hrs. Hexane was added to the reaction mixture and after filtration through a CELITE® 545 pad, the organic solution was washed with water, aqueous sodium bicarbonate (NaHCO3) and brine, and dried over anhydrous sodium sulfate (Na2SO4). After evaporating the solvent under reduced pressure the title compound (14) was obtained (0.29 g, 58% yield). The absolute configuration was determined by derivatization to a compound having known stereochemistry.
Reaction SMILES: [NH2:1][C:2]([CH:17]([CH3:19])[CH3:18])=[C:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O)[C:4]([O:6][CH3:7])=[O:5].CNS(C)(=O)=O.C(O)(C)(C)C.[C:31]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])#[N:32].CC(C)([O-])C.[Na+]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH:17]([CH3:19])[CH3:18])[N:1]=[C:31]([N:33]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:38])[N:32]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)C(C(=O)c1ccc(F)cc1)=C(N)C(C)C
Reactant: CN(C#N)S(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: CNS(C)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
2.50 g (9.42 mmol) of methyl 3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate were introduced into 2.08 g (28.3 mmol) of N-methylmethanesulphonamide and 3.49 g (47.1 mmol) of tert-butanol together with 3.79 g (28.3 mmol) of N-cyano-N-methylmethanesulphonamide. 1.87 g (18.8 mmol) of sodium tert-butoxide were added to this suspension at room temperature after the course of 15 min (exothermic). After 4 h at 76° C., the reaction suspension was poured onto 20 g of ice water. The suspension was stirred in an ice bath, and the precipitate was filtered off and washed with water (2×2.5 ml). After drying in a high vacuum, 1.61 g of methyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate were obtained in the form of a pale beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:27]([NH:26][CH3:25])=[O:28])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 51 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.1 eq of methyl isocyanate in dioxane/water (2:1) in the absence of sodium acetate. The crude product is purified by column chromatography (silica gel) eluting with a gradient of acetone/hexane to give pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)carbonyl]-1H-indole-3-methanamine (51%) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33].[Cl-].ClCC[N+](CC1C=CC=CC=1)(CC)CC>C(Cl)Cl.O>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][S:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)(=[O:42])=[O:43])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CC[N+](CC)(CCCl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 70 %

Procedure:
4-Methoxy-5-methyl-6-(l-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 6 ml of methylene chloride, a solution of 0.30 g (2.20 mmol) of potassium carbonate as a base in 4 ml of water was added, and 0.29 g (1.30 mmol) of p-nitrobenzenesulfonyl chloride and 0.05 g (0.2 mmol) of chlorobenzyltriethylammonium chloride as reaction reagents (XII) were added. The resultant mixture was allowed to react at room temperature for 2 hours. Further, the reaction mixture was refluxed under heat for 2 hours. After the reaction mixture was allowed to cool, its methylene chloride layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography to give 0.42 g (yield 70%) of 4-methoxy-5-methyl-6-(1-ethyl-5-(p-nitrobenzenesulfonyl) oxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 13) as an end compound which comes under the general formula (XI). Table 22 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31]O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:72]([O:71][C:69](=[O:70])[N:68]=[C:66]([NH:65][C:63]([O:62][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:64])[NH:67][CH2:31][CH2:30][O:29][C:28]1[CH:33]=[C:34]([F:35])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:26]([F:36])[CH:27]=1)([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 8 h
Yield: 128.5 %

Procedure:
To a solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (153 mg, 0.27 mmol) in THF (0.39 mL) were added PPh3 (107 mg, 0.41 mmol), 1,3-bis(tert-butoxycarbonyl)guanidine (144 mg, 0.55 mmol) and DIAD (85 μL, 0.41 mmol). After stirring overnight, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (80% EtOAc/hexanes) to afford tert-butyl(tert-butoxycarbonylamino)(2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethylamino)methylenecarbamate (279 mg), which was taken to the final step without further purification. MS (EI) m/z 804.5 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.I[CH3:16]>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][N:10]([CH3:16])[C:11]=2[CH:12]=1
Reactant: CI
Reactant: N#Cc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(C#N)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
Tetrahydrofuran (27 ml) was added to a flask containing sodium hydride (0.275 g, 6.89 mmol) and the mixture was stirred for 10 minutes at 0° C. 6-Bromo-1H-indazole-4-carbonitrile (1.39 g, 6.26 mmol) was added portionwise and the mixture was stirred for 10 mins until no further effervescence was seen. Iodomethane (0.431 ml, 6.89 mmol) was added and the mixture stirred at 0° C. for 1 h. The ice bath was removed and the flask was placed in a water bath at room temperature. The reaction remained stirring for 19 h and the mixture was then evaporated in vacuo. The residual solid purified by silica (100 g) cartridge using a gradient of ethyl acetate and cyclohexane to give the title compound as a white solid (370 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (139) (100 mg, 0.25 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:6][C:5]=1[CH2:19][OH:20])([CH3:3])=[CH2:2]>[Pd]>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[S:6][C:5]=1[CH2:19][OH:20])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: [Pd]
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)sc1CO

Procedure:
The solution of [3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (0.084 g, 0.282 mmole) is stirred under nitrogen gas in presence of 10% palladium on carbon (0.085 g) for 16 hours. The catalyst is removed by filtration, and the filtrate is concentrated to provide the titled compound as white solid, which is used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:59])[C:47]4[C:51]([CH:52]=3)=[N:50][N:49](C3CCCCO3)[CH:48]=4)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:59][C:8]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h
Yield: 24.9 %

Procedure:
3-Methyl-2-pyridinecarboxylic acid (11 mg, 0.08 mmol) in DMF (0.20 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) in DMF (0.20 ml) and DIPEA (0.030 ml). The reaction mixture was shaken for five minutes then treated with 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.20 ml). The reaction mixture was shaken then left to stand at room temperature overnight. Solvent was removed in vacuo and the product re-dissolved in methanol (1 ml) then applied to an SCX cartridge (1 g) which had been pre-rinsed with methanol. After 1 h, the cartridge was eluted with ammonia in methanol (2M, 2×3 ml). Fractions containing product were combined, dried and then further purified by Mass Directed Automated Preparative HPLC (Method D). Fractions containing product were combined and dried to give the title compound (5.5 mg) as a pale yellow gum.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[N:16][C:17]([NH:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]3)=[N:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@H:25]1[CH2:24][CH2:23][C@H:22]([NH:21][C:17]2[N:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:12][CH:13]=3)[N:18]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1

Procedure:
The tert-butyl [trans-4-({7-[(benzylamino)carbonyl]quinazolin-2-yl}amino)cyclohexyl]carbamate (780.0 mg, 2.0 mmol) was treated with TFA (2.3 g, 20.0 mmol) in DCM (15 ml) at 50° C. for 2 hours. Removal of solvent and TFA gave 758.0 mg of product without further purification. MS m/z, (APCI); 378.5 ([M+H]+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[C:3]=21)=[O:7]
Reactant: C1=CCCC=C1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C1=C1CCC2CC1
Temperature: 25 °C

Procedure:
To a solution of maleic anhydride (10.30 g) in toluene (100 ml) was added 1,3-cyclohexadiene (8.41 g). The mixture was refluxed for 3 hours. After cooling to 25° C., the solvent was evaporated at reduced pressure. The solid was recrystallized from EtOAC/hexane to yield bicyclo[2.2.2]oct-en-2,3-dicarboxylic anhydride as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:6]=1>O1CCCC1.CO.[Pd]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:6]=2)=[C:2]([F:1])[CH:26]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reaction time: 3 h
Yield: 77.8 %

Procedure:
3-[4-(2-Fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (243 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (6 ml), and 10% palladium on carbon (128 mg) was added thereto, followed by stirring under a hydrogen atmosphere for 3 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) and concentrated under reduced pressure to provide the titled compound as pale yellow powder (175 mg, 78.0%).
Reaction SMILES: [CH3:1][OH:2].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH:13]=[O:14])=[CH:7][NH:8]2.[C-]#N.[Na+]>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:13]([O:2][CH3:1])=[O:14])=[CH:7][NH:8]2
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Reactant: CO
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methanol (40 mL) solution of 4-bromo-1H-indole-3-carboaldehyde [Chem. Pharm. Bull. 33,3696 (1985)] (395 mg), sodium cyanide (432 mg) and manganese dioxide (15.3 g) were sequentially added and the mixture was stirred overnight at room temperature. To the reaction mixture, ethyl acetate (50 mL) was added and insoluble matters were removed. The filtrate was concentrated and water was added to the residue, and then the solution was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried and then concentrated. The residue was washed with diisopropyl ether and n-hexane and then concentrated to obtain the titled compound having the following physical properties (375 mg).