Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[F:34][C:35]([F:47])([F:46])[C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([S:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:46])[F:47])[CH:37]=3)(=[O:44])=[O:43])[CH2:20][CH2:19]2)=[CH:3][CH:2]=1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN(CC(O)COc2cccc3[nH]c4ccccc4c23)CC1
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a solution of 1-(9H-carbazol-4-yloxy)-3-piperazin-1-ylpropan-2-ol (0.2 g, 0.614 mmol) in DMF (4 mL), was added DIPEA (0.05 mL, 0.301 mmol) followed by the drop-wise addition of 3-trifluoromethylbenzenesulfonyl chloride (0.098 g, 0.61 mmol) at room temperature and the reaction mixture was stirred for 3 hours. Subsequently the reaction mixture was diluted with ethyl acetate (30 mL), washed with water and brine solution. The organic layer was dried on anhydrous Na2SO4, concentrated, and purified by precipitating the compound from dichloromethane by adding hexane, to give the required compound as a pale yellow colored solid (0.102 g, 30% yield). 1H NMR (400 MHz, DMSO): δ 2.30-2.90 (m, 6H), 3.00-3.30 (m, 4H), 4.00-4.30 (m, 4H), 5.00 (s, 1H), 6.61 (d, 1H, J=8 Hz), 7.00-7.20 (m, 2H), 7.25-7.40 (m, 2H), 7.42 (d, 1H, J=8.0 Hz), 7.80-8.00 (m, 2H), 8.06 (d, 1H, J=8 Hz), 8.20-8.30 (m, 2H), 11.26 (d, 1H, J=12 Hz). MS m/z: 534.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(OC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexylaminocarbonyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]1/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].CC(C)=O.[Cr](O)(O)(=O)=O>S(=O)(=O)(O)O>[C:13]([CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[CH:7]\[CH:3]1[CH:4]=[CH:5][CH2:6][C:2]1=[O:1])([OH:15])=[O:14]
Reactant: O=C(O)CCCC/C=C\C1C=CCC1O
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCCC/C=C\C1C=CCC1=O

Procedure:
A solution of 3.2 g. (0.5 mole) of 1-hydroxy-2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene (Example 1132) in 60 ml. of reagent acetone is treated dropwise with a total of 6 ml. of 8N chromic acid in sulfuric acid at 0° C. The oxidation is rather slow. The resulting mixture is dissolved in 200 ml. of water and the solution is extracted with six 50 ml. portions of ether. The combined ethereal extracts are dried over sodium sulfate and the solvent is evaporated at reduced pressure to yield the product as a yellow oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:31])[CH2:28][CH2:29][CH3:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CCCC(=O)O
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (60 mg, 60%), MS (ISP) m/z=397.3 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and butyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.[C:11](#[N:14])[CH:12]=C.C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>C(#N)CC.[Pd+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]=[CH:12][C:11]#[N:14]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Solvent: CCC#N
Product: N#CC=Cc1cccc(Br)c1
Yield: 9.9 %

Procedure:
The procedure described in Example 1 is repeated, except that 21.94 g (0.1 mol) of 3-bromobenzoyl chloride, 6.63 g (0.125 mol) of acrylonitrile, 35.37 g (0.1 mol) of tris-(2-ethylhexyl)-amine and 0.3046 g (0.001 mol) of bis-acetylacetonato)-palladium(II) in 50 ml of propionitrile are used. After a reaction time of 3 hours at 100° C., 2.05 g (0.0099 mol) of 3-bromocinnamonitrile are obtained, corresponding to a yield of 9.9% of theory; melting point 62° C. Analysis for C9H6NBr (molecular weight 208): calculated C 51.96%, H 2.91%, N 6.73%; found C 52.29%, H 2.95%, N 6.91%.
Reaction SMILES: [C:1]([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][CH:3]=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C.CCCCCC.C(=O)(O)[O-].[Na+].C(Cl)(=O)C1C=CC=CC=1>CC(C)=O.ClCCl.CO>[C:1]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: CC(C)=O
Product: O=C(c1ccccc1)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (11.1 g, 18.3 mmol) and acetone/water (1/1, 200 mL). Cool to about 0° C. in an ice bath and add sodium bicarbonate (10.6 g, 217.6 mmol). Warm to ambient temperature and slowly add a solution of benzoyl chloride (4.2 g, 365 mmol) in acetone (10 mL). After 18 hours, filter and dilute the filtrate with ethyl acetate. Extract the diluted filtrate with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol 95/5 to give 1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine: Rf=0.81 (silica gel, dichloromethane/methanol 95/5).
Reaction SMILES: CO.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([N+:25]([O-])=O)[CH:13]=1>[Fe].C(O)(=O)C>[NH2:25][C:14]1[CH:13]=[C:12]([C:4]2[O:3][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:5]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Temperature: 25 °C

Procedure:
0.69 g of iron powder was added to a suspension of 7.0 mL of methanol and 7.0 mL of acetic acid containing 1.4 g of tert-butyl 4-(benzofuran-2-yl)-2-nitrobenzoate and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the obtained residue and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 0.88 g of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate as white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[NH:7][C:8]=1[Br:9].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:9][C:8]1[N:7]=[C:6]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:4]=1[Br:3]
Reactant: Brc1nc(C2CCC2)[nH]c1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C2CCC2)nc(Br)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.7 %

Procedure:
A 250 mL round-bottom flask was purged with nitrogen and charged with NaH (95%, 0.2 g, 8.3 mmol). THF (10 mL) added, and the mixture cooled to 0° C. After 5 minutes, a solution of 4,5-dibromo-2-cyclobutyl-1H-imidazole (1.76 g, 6.29 mmol, ˜40% purity) in THF (20 mL) was added dropwise from an addition funnel over 5 minutes. The reaction was stirred at 0° C. for 35 minutes and SEMCl (1.8 mL, 10.2 mmol) was then added dropwise over 2 minutes. After 5 minutes, ice bath was removed, and the reaction stirred at room temperature for 4 hours. LCMS indicated complete reaction. The reaction was then carefully quenched with water (1.5 mL). Heptane (250 mL) was added and organic layer was washed with water (200 mL). The aqueous layer was extracted with heptane (100 mL), and the combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to give 2.14 g of crude material. The crude material was purified by flash chromatography (SiO2; EtOAc in heptane) to afford 4,5-dibromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.43 g) as a yellow oil: LCMS (m/z) 408.9 (MH+), tR=1.25 minutes.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:5][CH:4]=1.C([C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH2:30][S:31](Cl)(=[O:33])=[O:32])C>N1C=CC=CC=1>[CH2:19]([C:18]1[CH:23]=[CH:24][CH:25]=[CH:10][C:11]=1[C:29]1([CH2:30][S:31]([N:2]([C:3]2[CH:4]=[CH:5][C:6]([N:9]3[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]4[C:18]5[C:23]([CH:24]=[CH:25][C:10]3=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:7][CH:8]=2)[CH3:1])(=[O:32])=[O:33])[CH:28]=[CH:38][CH:37]=[CH:36][CH2:35]1)[CH3:20]
Reactant: CNc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CCc1ccccc1CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCc1ccccc1C1(CS(=O)(=O)N(C)c2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)C=CC=CC1
Yield: 27.9 %

Procedure:
5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40 mg, 0.121 mmol) obtained in Example 198, (1), and 2-ethylbenzylsulfonyl chloride (132 mg, 0.605 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to obtain the title compound (10 mg, yield 16%) as white crystals.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@@H:28](O)[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[NH:13][N:12]([C@@H:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH3:29])[NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: C[C@H](O)c1ccccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1Cl)N1Nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow gum (3.1 mg, 17%). MS (m/e): 421.4 (MH+).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[S-:11][C:12]#[N:13].[NH4+].C(O)C>O>[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:12]([NH2:13])=[S:11]
Reactant: N#C[S-]
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1NNC(N)=S

Procedure:
A mixture of 15.9 g. (0.1 moles) of o-tolylhydrazine hydrochloride, 15.2 g. (0.2 moles) of ammonium thiocyanate, 300 ml. of ethanol and 30 ml. of water are heated at reflux temperature for 24 hours, the solvent is removed by distillation at atmospheric pressure, and sufficient water added to cause precipitation. The aqueous suspension is filtered and the solid residue recrystallized from aqueous ethanol affording 15 g. (85%) of 1-(o-tolyl)-3-thiosemicarbazide, m.p. 158°-160° C.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][S:3]1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30]>ClCCl.C(OCC)(=O)C.O>[CH2:32]([O:31][C:29](/[N:1]=[C:2]1\[S:3][CH:4]=[CH:5][N:6]\1[CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:30])[CH:33]=[CH2:34]
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2ccsc2=N)CC1
Reactant: C=CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)/N=c1\sccn1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96 %

Procedure:
To a solution of tert-butyl 4-((2-imino-1,3-thiazol-3(2H)-yl)methyl)-1-piperidinecarboxylate (0.9 g) obtained in Example 139a) and triethylamine (0.93 ml) in dichloromethane (10 ml) was added allyl chloroformate (0.35 ml) under ice-cooling, and mixed at 0° C. for 12 hours. Ice chips were added to the reaction mixture to stop the reaction, and diluted with ethyl acetate and water. The organic layer was collected by separation, washed with saturated sodium bicarbonate water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless solid (1.1 g, 96%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[NH:6][N:5]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][C:19]=1[CH3:28])(=[O:17])[CH3:16].Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15](=[O:17])/[CH:16]=[CH:13]/[C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][N:5]=[C:4]3[CH3:3])=[C:19]([CH3:28])[CH:20]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(C)c1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N)ccc1C(=O)/C=C/c1ccc2[nH]nc(C)c2c1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
To a solution of KOH (1.5 g, 26 mmol) in 20 mL ethanol were added 3-methyl-1H-indazole-5-carbaldehyde (see Note 1 for synthesis) (0.850 g, 5.3 mmol) and commercially available N-(4-acetyl-3-methylphenyl)acetamide (1.0 g, 5.3 mmol). The reaction mixture was heated to 80° C. for 24 hours and then cooled down to room temperature. After acidification with 1N HCl, the mixture was brought to pH 8 with saturated aqueous NaHCO3 and extracted twice with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by SiO2 flash chromatography (60:40 to 50:50 hexanes/ethyl acetate) to afford (E)-1-(4-amino-2-methylphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (0.500 g, 32%). 1H NMR (400 MHz, d6-DMSO): δ 12.8 (s, 1H), 8.12 (s, 1H), 7.81 (dd, 1H), 7.78 (d, 1H), 7.61 (d, 2H), 7.48 (d, 1H), 6.45 (m, 2H), 5.88 (br s, 1H), 3.06 (s, 3H), 2.42 (s, 3H); MS (EI) for C18H17N3O: 292.3 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=3[CH3:25])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:27]1C=C(C2SC(NC(=O)C)=NC=2C)C=CC=1S(C)(=O)=O.FC1C=C(C2SC(NC(=O)CC)=NC=2C)C=CC=1S(C)(=O)=O>>[N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21][C:22](=[O:24])[CH2:23][CH3:27])=[N:18][C:17]=3[CH3:25])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Agent: CCC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1

Procedure:
The title compound is prepared via an analogous procedure to N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 80) by replacing N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in this example with N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide (159).
Reaction SMILES: Cl.[F-:2].[F-].[F-].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[OH-].[NH4+]>C(O)C>[F-:2].[F-:2].[F-:2].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccccc1N
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 220.8 %

Procedure:
A concentrated hydrochloric acid solution (120 mL) was added to a suspension of 4-amino-3-nitrobenzene trifluoride (20.06 g) and ethanol (400 mL) in air. The mixture was heated to 80° C. with stirring. After reduced iron (27.09 g) was gradually added thereto over a period of 15 minutes, the mixture was heated to reflux for 1 hour with stirring. After the mixture was cooled on ice, the resulting solution was neutralized with aqueous ammonium hydroxide and then extracted with dichloromethane. The extract was washed with water, concentrated, and purified by silica-gel column chromatography to yield 3,4-diaminobenzene trifluoride (12.495 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CCCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC(C)(C)C)OC3=O)cc(F)c21
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.770 ml, 7.86 mmol) is added to (R)-[3-(7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.400 g, 1.05 mmol) and triethylamine (0.726 ml, 5.24 mmol) in dichloromethane (5 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a dark yellow solid. HPLC r.t. 5.28 min; MS for C20H26FN3O5 m/z 408.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)=[O:9])=[C:6]([NH:20][C@H:21]([C:23]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:27](=[O:35])[C:26]3=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]3[N:24]=2)[CH3:22])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:9])=[C:6]([NH:20][C@H:21]([C:23]2[N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:27](=[O:35])[C:26]3=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]3[N:24]=2)[CH3:22])[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(CNC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)NCc3cccc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 36 %

Procedure:
(S)-4-Amino-N-(3-methoxybenzyl)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (103 mg, 0.20 mmol) was treated with boron tribromide (1M in dichloromethane, 0.85 ml, 0.85 mmol) in dichloromethane (8 ml) according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 37 mg (36% yield) as a solid. Purity 98%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH:39]=[CH:38][NH:37][N:36]=2)O1>CN(C=O)C.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:39]=[CH:38][NH:37][N:36]=4)=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: N#Cc1c(O)c2c(-c3ccc(I)cc3)csc2[nH]c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2c(-c3ccc(-c4cc[nH]n4)cc3)csc2[nH]c1=O
Temperature: 130 °C

Procedure:
To a suspension of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol) and MgO (18 mg, 0.45 mmol) in 2 mL DMF and 2 mL dioxane, was added Cs2CO3 (0.45 mL, 1M solution in H2O), followed by 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (38 mg, 0.2 mmol), and Pd(PPh3)4 (10 mg, 0.008 mmol). The reaction was heated to 130° C. using microwave reactor for 15 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 335 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ 6.61 (s, 1H), 7.00 (s, 1H), 7.43 (d, J=8.42 Hz, 2H), 7.49 (d, J=8.42 Hz, 2H), 8.04 (s, 1H).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:21])[CH3:20])[CH2:10][CH:9]1[CH3:28])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:28][CH:9]1[CH2:10][CH:11]([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:21])[CH3:20])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8]1
Reactant: CC(=O)N(c1ccccc1)C1CC(C)N(Cc2ccccc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N(c1ccccc1)C1CC(C)Nc2ccccc21
Yield: 105.7 %

Procedure:
A solution of N-(1-benzyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylacetamide (50 mg) and ammonium formate (85 mg) and palladium on activated carbon 10% in ethanol (2 ml) were warmed to reflux for 1 hour. The solution was filtered on celite and the solvent was removed to afford N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylacetamide (40 mg).