Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([CH2:10][C:11]3[NH:12][C:13](=[O:26])[C:14]4[S:19][C:18]([C:20]5[CH:21]=[N:22][NH:23][C:24]=5[CH3:25])=[CH:17][C:15]=4[N:16]=3)[CH2:6]2)[O:4]CC1.Cl.C(=O)([O-])O.[Na+]>CC(O)C>[CH3:25][C:24]1[NH:23][N:22]=[CH:21][C:20]=1[C:18]1[S:19][C:14]2[C:13](=[O:26])[NH:12][C:11]([CH2:10][N:7]3[CH2:8][CH2:9][C:5](=[O:4])[CH2:6]3)=[N:16][C:15]=2[CH:17]=1
Reactant: Cc1[nH]ncc1-c1cc2nc(CN3CCC4(C3)OCCO4)[nH]c(=O)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1[nH]ncc1-c1cc2nc(CN3CCC(=O)C3)[nH]c(=O)c2s1
Temperature: 90 °C
Yield: 86.9 %

Procedure:
A mixture of 2-(1,4-dioxa-7-azaspiro[4.4]non-7-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4 (3H)-one (150 mg) produced in Example 39, step D, 6M hydrochloric acid (3 mL) and propan-2-ol (3 mL) was stirred with heating at 90° C. for 5 hr. Saturated aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, and washed successively with ethyl acetate (3 mL) and water (3 mL). The obtained pale-brown solid was crystallized from methanol/propan-2-ol/hexane to give the title compound (115 mg) as a pale-brown solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]([CH:12]=O)[CH2:5]1)[CH:2]=[CH2:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:4]1[CH2:8][CH:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]([CH2:12][N:24]2[CH2:25][CH2:26][CH:21]([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: C=CCN1CC(C=O)C(C2CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of 1.8 g (10 mmol) of 1-allyl-3-(RS)-formyl-4-(SR)-(cyclopropyl)pyrrolidine and 2.68 g (15 mmol) of 4-(4-fluorophenyl)piperidine in 30 mL of dichloroethane at rt was added portionwise 6.36 g (30 mmol) of sodiumtriacetoxyborohydride. After stirring for 3 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd K2CO3. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, ethyl acetate:hexanes, 1:3) to give 2.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(CN3CCNCC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.59 mmol, 1.00 equiv) and dichloromethane (20 mL). Trifluoroacetic acid (2.5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.300 g (41% yield) of 1-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 286 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[C:17]([O:21][C:22](=[O:40])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:17]([O:21][C:22](=[O:40])[NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]3[N:14]=[CH:15][N:16]=[C:4]3[N:3]=2)=[CH:29][CH:30]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Clc1nc2ncnn2cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ncnn3cc2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 47.7 %

Procedure:
A mixture of compound 3-4 (60 mg 0.24 mmol), [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid tert-butyl ester (100 mg, 0.3 mmol), aq.Na2 CO3 (2M, 0.70 mmol, 0.35 mL) and Pd(DPPF)Cl2 (10 mg) in dioxane (3 mL) was heated at 100° C. in microwave system under N2 atmosphere for 30 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 46 mg of 3-5. MS (ESI) m/e (M+H) 402.1
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2].[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:21](=[O:22])[CH:20]([CH3:19])[C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[O:25])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCN1C(=O)[C@@H](N)CN(C(C)=O)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CCN1C(=O)[C@@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)CN(C(C)=O)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:31][O:32][NH:33][CH3:34].O>C(Cl)Cl>[CH3:31][O:32][N:33]([CH3:34])[C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a suspension of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (3 g, 12.33 mmol) in DCM (35 mL) was added CDI (4.00 g, 24.66 mmol) portion-wise. The resulting mixture was stirred for 1 hour, and then O,N-dimethylhydroxylamine hydrochloride (1.804 g, 18.50 mmol) was added, and the mixture was stirred at RT for 16 hours. Water (30 mL) was added, and the mixture was stirred for 1 hour and then extracted with DCM (50 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to afford tert-butyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (3.3 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]=[N:9]1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: CC(C(=O)O)c1ccc(N2CCC=N2)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C(=O)O)c1ccc(-n2cccn2)c(Cl)c1

Procedure:
252 mg (1 mmole) of 2-[3-chloro-4-(2-pyrazolin-1-yl)phenyl]propionic acid are heated to the boil for 8 hours with 250 mg of active manganese dioxide and 1 g molecular sieve 4 A*) in 10 ml of toluene. Filtration is effected, followed by extraction first with 1 N hydrochloric acid and then with 1 N sodium hydroxide. The aqueous alkaline extract is acidified and subsequently extracted with benzene; the resulting organic phase is dried to yield 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid (m.p. 83° to 85° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[CH:17]1([CH2:16][O:1][C:2]2[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([O:8][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Cc1cc(O)cc(C)c1C(=O)O
Product: Cc1cc(OCC2CC2)cc(C)c1C(=O)OCC1CC1

Procedure:
Using 4-hydroxy-2,6-dimethylbenzoic acid and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CO.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccccc3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 39.3 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, 0.55 mmol), phenylboronic acid (102 mg, 0.83 mmol), Pd2(dba)3 (33 mg, 0.056 mmol), X-phos (105 mg, 0.22 mmol) and K2CO3 (226 mg, 1.63 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product. This was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol and three drops of concentrated HCl added. The mixture was stirred for 5 minutes, then concentrated in vacuo to give a light yellow solid (80 mg, 40%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.87 (s, 1H), 8.37 (d, 1H, J=2.4 Hz), 8.10 (d, 1H, J=1.8 Hz), 8.01-7.98 (m, 2H), 7.60-7.53 (m, 4 h), 6.45 (d, 1H, J=7.8 Hz), 6.30 (d, 1H, J=8.4 Hz), 4.28-4.24 (m, 1H), 3.67-3.47 (m, 2H), 2.20-1.80 (m, 4 h), 1.20 (d, 1H, J=6.3 Hz). LC-MS: [M+H]+, 371, tR=1.97 min, HPLC: 97.57% at 214 nm, 99.43% at 254 nm, tR=7.473 min.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]([NH2:26])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C.N1CCCCC1>C(O)(C)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22](=[O:25])[NH2:26])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: C=CC(N)=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: NC(=O)CCN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C

Procedure:
1.00 gram (3.62 millimoles) of 4-(5H-dibenzo-[a,d]cyclohepten-5-yl)piperidine, 0.26 gram (3.62 millimoles) of acrylamide, 0.04 gram (0.36 millimole) of triethylamine and 20 milliliters of isopropyl alcohol were stirred together at reflux temperature while protected from atmospheric moisture. A TLC analysis of a sample of the reaction mixture indicated presence of some piperidine compound but no acrylamide. 50 milligrams (0.7 millimole) of acrylamide in 1 milliliter of isopropyl alcohol was added and the reaction continued at reflux temperature for a total of about 3.5 hours. The reaction mixture was allowed to cool to room temperature and the solvent then removed in vacuo to obtain the desired 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(2-carbamoylethyl)piperidine product as residue. The crude product was crystallized from methylene chloride/hexane, then dried in vacuo overnight at 100° C. to obtain 900 milligrams (72 percent yield) of product, m.p. 135°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)cc1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 90%). 1H NMR (200 MHz, CDCl3): δ 3.17 (s, 4H), 3.78 (s, 7H), 4.15 (m, 3H), 6.85-6.96 (m, 4H), 7.29-7.49 (m, 2H), 7.74-7.77 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C:9]([C@@H:10]([CH3:30])[CH2:11]2)=[CH:8][C:7](=[O:31])[CH2:6][CH2:5]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:32])[C:9](=[CH:8][C:7](=[O:31])[CH2:6][CH2:5]2)[C@@H:10]([CH3:30])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:35])[CH3:34]
Reactant: COCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Product: COCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
As described in Example 5(c), 600 mg of 11β,21-dihydroxy-17methoxyacetoxy-6α-methyl-4-pregnene-3,20-dione is reacted with acetic anhydride, worked up, and chromatographed, thus isolating 480 mg of 21-acetoxy-11β-hydroxy-17-methoxyacetoxy-6α-methyl-4pregnene-3,20-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([CH2:15][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Fc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(SCc2cccc(F)c2)cc1
Yield: 54 %

Procedure:
Prepared in analogy to example 8 from 4-nitrothiophenol and 3-fluoro-benzylbromide. Yellowish solid. Yield=54%.
Reaction SMILES: C(Cl)(=O)C.[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:8]1[CH2:9][CH2:10][N:5]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:7]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.38-7.50 (m, 7H), 7.28-7.38 (m, 4H), 6.87-6.91 (m, 2H), 4.74 (s, 4H), 3.39-3.90 (m, 4H), 3.01-3.17 (m, 4H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[Li]C(C)(C)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30](OC)=[O:31])=[N:28][CH:29]=1>CCOCC>[C:12]([O:11][C:10](=[O:16])[NH:9][C:4]1[C:5]([C:30](=[O:31])[C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:22])[F:35])=[CH:29][N:28]=2)=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(F)(F)F)cn1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cccc(C(=O)c2ccc(C(F)(F)F)cn2)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (443.3 mg, 1.986 mmol) in ether (5 mL) under N2 was added t-BuLi (2.6 mL, 4.42 mmol). The reaction mixture was stirred for 2 h, and then cooled to −78° C. To the reaction mixture was added a solution of methyl 5-(trifluoromethyl)picolinate (501.3 mg, 2.44 mmol) in ether (10 mL) dropwise via cannula over 5 min. After 2 h, the reaction mixture was warmed to room temperature, stirred for an additional hour, and then the reaction was quenched by the addition of water with vigorous stirring. The reaction mixture was diluted with EtOAc, the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield a yellow solid. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.83-8.88 (1H, m), 8.24 (1H, d, J=8.4 Hz), 8.07 (1H, dd, J=8.4, 1.8 Hz), 7.25 (1H, d, J=1.5 Hz), 7.18-7.24 (1H, m), 7.09 (1H, dd, J=8.0, 1.7 Hz), 6.95 (1H, s), 3.93 (3H, s), 1.25 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](N(OC)C)=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([Mg]Br)=[CH2:26]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](=[O:20])[CH:25]=[CH2:26])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-Butyl 4-(tert-butoxycarbonylamino)-5-(methoxy(methyl)amino)-5-oxopentanoate (4.12 g, 12.2 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to −70° C. under nitrogen. Vinylmagnesium bromide (37 mL, 1.0 M soln in THF, 3.0 eq) was added dropwise. The reaction stirred for 30 min at −70° C. and was then the cooling bath was removed and the reaction stirred at room temperature overnight. The mixture was colled on in an ice bath and acetic anhydride (20 mL) was added, followed by methanol (27 mL). The mixture was concentrated under pressure to a small volume and then diluted with ethyl acetate. The reaction mixture was washed successively with water and brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 1:4 ethyl acetate:hexanes to yield (S)-tert-butyl 4-(tert-butoxycarbonylamino)-5-oxohept-6-enoate (0.94 g) as a yellow oil. 1H NMR (CDCl3): 6.48-6.45 (m, 2H), 5.94 (m, 1H), 5.29 (m, 1H), 4.70 (m, 1H), 2.38-2.05 (m, 2H), 2.02 (m, 1H), 1.70 (m, 1H), 1.45 ppm (s, 18H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:11]2)=[CH:6][CH:5]=1.[N+]([NH:28][C:29](N)=[O:30])([O-])=O.CN(C)C=O>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:29]([NH2:28])=[O:30])[CH2:21][CH2:20]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(N3CCN(C(N)=O)CC3)c3ccccc32)cc1
Yield: 85.4 %

Procedure:
A solution of 1-(4-methoxyphenyl)-3-(1-piperazinyl)-1H-indazole hydrochloride (5.0 g, 0.01 mol), nitrourea (4.0 g, 0.04 mol) and dimethylformamide (200 ml) was warmed on a steam bath for 2 hours. The reaction mixture was poured into H2O and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was dried with MgSO4 and concentrated to 5.3 g of an oil. Crystallization was achieved with toluene affording 3.3 g (65%) of a powder. The powder was recrystallized again from toluene to afford 3.0 g of 4-[1-(4-methoxyphenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 155°-157° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]12([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=3[O:2]1)[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: O=C1CCCC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)OC1(CCCC1)O2
Reaction time: 18 h

Procedure:
Catechol (11 g) and cyclopentanone (9 ml) were heated under reflux in toluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After 18 hours, the mixture was concentrated and purified by chromatography (silica gel, heptane/ethyl acetate 4:1). This resulted in the product with the molecular weight of 176.22 (C11H12O2); MS (ESI): 177 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1ccccc1-c1ccc(F)c(N)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1ccc(F)c(Br)c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A warm solution of 3′-amino-4′-fluorobiphenyl-2-carbonitrile (4.24 g, 20 mmol) in 1,4-dioxane (30 ml) was treated with 48% hydrobromic acid (100 ml) and the resulting suspension stirred and cooled to 3° C. (internal temp). A solution of sodium nitrite (1.59 g, 23 mmol) in water (4 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before adding a cooled (5° C.) solution of copper(I) bromide in 48% hydrobromic acid (30 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (2×200 ml). The organics were combined, washed with 5% aqueous sodium sulfite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification on silica, eluting with isohexane on a gradient of ethyl acetate (2-12%) afforded 3′-bromo-4′-fluorobiphenyl-2-carbonitrile as a white solid (2.5 g, 45%): δH (400 MHz, CDCl3) 7.22-7.27 (1H, m), 7.45-7.53 (4H, m), 7.66 (1H, td, J 8 and 2), 7.73 (1H, dd, J 8 and 2), 7.77 (1H, dd, J 8 and 2).