Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-])=O>[Cu]>[C:23]1([N:20]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:6]=[CH:5][C:4]([C:8]3[CH:13]=[CH:12][C:11]([N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]4[CH:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=5)[CH:13]=[CH:12][CH:11]=4)=[CH:10][CH:9]=3)=[CH:3][CH:2]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Ic1cccc(-c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cccc(N(c3ccccc3)c3ccc(-c4ccc(N(c5ccccc5)c5cccc(-c6ccccc6)c5)cc4)cc3)c2)cc1
Yield: 78.89 %

Procedure:
300-ml reactor was charged with 10 q (0.0298 mol) of N,N'-diphenylbenzidie, 25 g (0.0893 mol) of m-iodobiphenyl, 12.3 g (0.0891 mol) of potassium carbonate, 2.6 g of copper powder, and 150 ml of nitrobenzene. In an argon stream, the contents were heated under reflux for 24 hours. At the end of reaction, the insoluble was removed by filtration and the solvent was distilled off from the filtrate. The still residue was purified through a silica gel column with a 5/1 mixture of n-hexane and ethyl acetate, obtaining 15 g of N,N'-diphenyl-N,N'-di(3-biphenylyl)benzidine of primary purity grade (yield 78.89%. It was further purified by recrystallization from toluene and train sublimation, obtaining 10.6 g of a 99.9% pure product (yield 55.6%). Further purification by sublimation yielded a 99,99% pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetate (351.7 mg, 0.732 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (173.0 mg, 0.732 mmol), Et3 N (122.4 μl, 0.878 mmol) in DMF (5.2 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:5, v/v) as eluent to afford methyl 2-[[1-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred solution of this compound in THF (5.6 mL) and H2O (1.4 mL) was added LiOH (45.7 mg, 1.91 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3, and treated with sat. NH4Cl, washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et2O—CHCl3-MeOH to afford 193.8 mg (59%) 40 as a white crystalline powder. mp 125–128; IR (KBr) 1716, 1600, 1533, 1255 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.67–2.03 (m, 4H), 2.50 (s, 3H), 3.33–3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27–4.31 (m, 2H), 4.42–4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87–6.95 (m, 3H), 7.11–7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 519 (M++1); Anal. Calcd for C28H30N4O6.1/2H2O: C, 63.75; H, 5.92; N, 10.62. Found: C, 63.61; H, 5.94; N, 10.27.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([CH3:11])([C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:5].O>CCOCC>[Br:1][CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:4]([CH3:11])([CH3:5])[CH3:3]
Reactant: BrBr
Reactant: CCCC(=O)C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CCC(Br)C(=O)C(C)(C)C
Reaction time: 14 h
Yield: 109.7 %

Procedure:
Slowly add bromine (10.87 ml, 212.15 mmol) to 2,2-dimethylhexane-3-one (27.20 g, 212.15 mmol) in ether (200 ml) and allow the reaction to stir for 14 h. Combine the reaction mixture with water (200 ml) and partition. Dry the organic layer over Na2SO4, filter and then concentrate the filtrate to provide the title compound as a yellow oil (48.2 g, quant). 1NMR (400 MHz, CDCl3) δ ppm: 1.01 (t, J=7.6 Hz, 3H), 1.27 (s, 9H), 2.03 (m, 2H), 4.58 (t, J=7.2 Hz, 1H). High Res. ES-MS: 207.0348; calc. for C8H15BrO+H, 207.0384.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20])=[O:34]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Nc1cc(C(F)(F)F)ccc1F
Yield: 80 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 2-fluoro-5-trifluoromethyl-phenylisocyanate to afford the title compound, yield=80%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:12][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Chloro-6-fluoro-2H-isoquinolin-1-one (prepared according to WO 2007/012422; 52.2 g) was dissolved in THF (1 L). After addition of silver carbonate (145.5 g) and benzyl bromide (40.6 mL), the mixture was stirred at room temperature overnight. Another 6.2 mL of benzyl bromide were added and the mixture was stirred at 70° C. for 2 h. After cooling down to room temperature, the reaction mixture was diluted by addition of 1 L of ethyl acetate and filtered over celite. The filter cake was washed thoroughly, the organic layer was evaporated and subjected to silica gel chromatography (n-heptanes: methyl tert. butyl ether) to give 27.8 g of the title compound (38). Rt=3.73 min (Method 1). Detected mass: 288.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:16][CH:15]3[N:17](C(OC(C)(C)C)=O)[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:25].CCOCC>>[ClH:25].[ClH:25].[N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:16][CH:15]3[NH:17][CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: Cl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2CC3CCC(C2)N3)cn1
Yield: 55 %

Procedure:
The product from Example 10A was treated with 1M HCl/ether to provide the title compound (55% yield). 1H NMR (DMSO-d6, 300 MHz) δ 1.9-2.0 (m, 4H), 3.4-3.5 (m, 2H), 4.00 (d, J=11 Hz, 2H), 4.20 (br s, 2H), 7.5-7.6 (m, 1H), 8.2-8.3 (m, 2H), 9.6-9.7 (br s, 3H, exchangeable).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]2)=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@@H:18]2[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C:3]3=[O:2])=[CH:14][CH:13]=2)=[O:17])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
7.3 12.64 g (36.98 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride are suspended in 1200 ml of dichloromethane, and 5.4 ml of triethylamine are added with cooling in an ice bath. The solution of 5.96 g (38.83 mmol) of 4-chlorophenyl isocyanate in 100 ml of dichlormethane is subsequently added dropwise to the mixture at 2° C. over the course of 1.5 hours, and the reaction solution is then left to stir for a further 30 minutes with ice cooling. The dichloromethane solution is then washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the methylene chloride solution has been evaporated to ⅓ of the original volume in a rotary evaporator, the precipitated product is filtered off, washed with 50 ml of petroleum ether and dried in a desiccator, giving 14.6 g (86%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (“A8”) as a white powder, ESI 459; m.p. 216°.
Reaction SMILES: [CH:1](/[OH:11])=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CC([O:16]O)(C)C>C(Cl)Cl>[CH2:4]([C@@H:3]1[O:16][C@H:2]1[CH2:1][OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)(C)OO
Reactant: CCCCCCCC/C=C/O
Solvent: ClCCl
Product: CCCCCCC[C@@H]1O[C@H]1CO
Temperature: -20 °C
Reaction time: 2.25 h
Yield: 71 %

Procedure:
A solution of Ti(O-i-Pr)4 (0.6 ml, 0.57g, 2.0 mmole) and (+)-DET (0.45 g, 2.2 mmole) in CH2Cl2 (10 ml) was cooled to -20° C. in a CCl4 -Dry Ice bath. trans-1-Decen-1-ol (0.312 g, 2.0 mmole) in CH2Cl2 (1 ml) was added followed by addition of TBHP (4.0 mmole in toluene). The resulting solution was stirred at -20° C. for 2.25 hr and then was quenched by stirring with sat'd aq. Na2SO4 (2 ml) and ether (80 ml) for one hour. The mixture was filtered through Celite, dried (MgSO4), filtered, and concentrated. The crude product was chromatographed over silica gel (11.5 g, 10% acetone-hexane, 6 ml fractions) giving 0.244 g of 35 (1.42 mmole, 71%) which contained traces of a more polar impurity and a less polar impurity. This material was crystalline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[C:7]#N.[H-].C([Al+]CC(C)C)C(C)C.[O:21]1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=[O:21]
Reactant: C1CCOC1
Reactant: N#Cc1cc(Br)ccc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=Cc1cc(Br)ccc1I
Temperature: -80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-iodobenzonitrile (5.00 g, 16.00 mmoles) in anhydrous tetrahydrofuran (80 ml) at −80° C. is added diisobutyl aluminium hydride (16.0 ml, 16.0 mmoles, 1M solution in toluene) dropwise over 10 minutes. The reaction mixture is stirred at −80° C. for a 1 hour, then allowed to warm to ambient temperature and stir overnight. Additional diisobutyl aluminium hydride (16.0 ml, 16.0 mmoles, 1M solution in toluene) is next added dropwise at room temperature, and the reaction mixture further stirred for 1 hour. After careful quenching with 2M hydrochloric acid (cooling in ice bath), the crude product is extracted with ethyl acetate (×2), then all organics are combined and dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure then purified by flash column chromatography (isohexane to 10% ethyl acetate in isohexane eluant) to afford 5-bromo-2-iodobenzaldehyde (0.85 g).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].F[C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O>CS(C)=O>[CH3:6][O:5][C:1]([C:2]1[S:3][C:12]2[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[CH:8][C:9]=2[CH:10]=1)=[O:4]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: COC(=O)CS
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2s1
Yield: 65.6 %

Procedure:
To a solution of methyl thioglycolate (1.29 mL, 14 mmol, 1.1 eq.) in 22 mL of DMSO was added Nail 50% (0.972 g, 20 mmol, 1.56 eq.) and the mixture was stirred for 5 Min., before 2-fluoro-4-methoxybenzaldehyde (2.00 g, 13 mmol) was added (strongly exothermic). When the internal temperature had reached again 25° C., the reaction mixture was poured onto crashed ice and the precipitate filtered off, washed with water, and dried to obtain 1.896 g of the title compound as light yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]#[CH:15])[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[C:14]=[CH2:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: C=C=Cn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 37.6 %

Procedure:
The title compound was prepared as pale brown crystals in 37.6% yield in a similar procedure to that described in Example 44 by using 7-chloro-2,3-dimethyl-1-(2-propynyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:4][N:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(Cc2cccc(CC(=O)OC(C)(C)C)c2)o1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nnc(Cc2cccc(CC(=O)O)c2)o1
Reaction time: 2 h
Yield: 22.5 %

Procedure:
To a mixture of tert-butyl 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetate 1106 (0.127 g, 0.44 mmol) in dioxane (3 mL) was added 4N HCl in dioxane (1 mL) and stirred under an atmosphere of Argon for 2 hours. The volatiles were removed under reduced pressure and the residue diluted with water (5 mL) and the pH adjusted to 12 with 2.5 N NaOH. The mixture was washed with dichloromethane (4×2 mL) and the pH adjusted to 6 with 1 N HCl. The mixture was extracted with EtOAc (3×2 mL) and the organic layers combined, washed with brine and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure to give 0.023 g of 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetic acid 1107.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[NH:19]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:17][CH:18]1[NH:19][CH:20]([CH3:24])[CH2:21][N:22]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:23]1
Reactant: CC1CNCC(C)N1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC(C)N1
Yield: 58.4 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.3 g, 10 mmol), 2,6-dimethylpiperazine (1.14 g, 10 mmol), and EDC (3.82 g, 20 mmol) and DMAP (catalytic) in 20 ml dichloromethane was stirred at room temperature overnight, concentrated, added water and extracted with ethyl acetate 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.9 g of desired product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O.CO.[ClH:21]>C(OCC)(=O)C>[NH2:12][C:7]1[C:8]([Cl:21])=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[F:1]
Reactant: Cl
Reactant: O=[N+]([O-])c1cnccc1NCc1ccccc1F
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1c(NCc2ccccc2F)ccnc1Cl
Reaction time: 0.5 h

Procedure:
A mechanically stirred solution of 4-[(2-fluorobenzyl)amino]-3-nitropyridine (12.31 g, 49.8 mmol) in concentrated hydrochloric acid (118 ml) was heated to 90° under a nitrogen atm. Stannous chloride dihydrate (55.56 g, 246 mmol) was added in small portions over a 5 min period (the oil bath was removed until the reaction subsided). After an additional 30 min at 90°, the reaction mixture was cooled, diluted with water (200 ml) and spin evaporated in vacuo. The residue was diluted with water (200 ml) and cooled in an ice-bath, while concentrated ammonium hydroxide was added to adjust the pH to 7-8. The solids were collected and allowed to air dry overnight. The solid was treated with ethyl acetate and filtered (12×200 ml), the combined extracts were washed with water, dried (sodium sulphate) and spin evaporated in vacuo. The residue was combined with the product from a separate reaction (12 g, 48.5 mmoles) and dissolved in ethyl acetate. This solution was added to Silica Gel 60 and spin evaporated in vacuo. The residual solids were introduced to a column (5 cm×30 cm) of Silica Gel 60 wetted with ethyl acetate. The column was eluted with ethyl acetate using flash chromatography. The appropriate fractions were combined and spin evaporated in vacuo to give 20.8 g (84%) of 3-amino-2-chloro-4-[2-fluorobenzyl)amino]pyridine as a white solid, mp.=185°-187°; UV (0.1M hydrochloric acid+5% methanol), λmax 233 nm (ξ17900), 302 nm (ξ14900); (pH 7.0 buffer+5% methanol), λmax 262 nm (ξ11200), (0.1N sodium hydroxide+5% methanol), λmax 262 nm (ξ10700), 1H nmr (DMSO-d6): δ7.36-7.15 (complex m, 5H,Ar+pyridine H-6), 6.35-6.30 (d,1H,pyridine H-5), 6.27-6.33 (overlapping,1H,NH). 4.84 (2,2H,NH2), 4.41 (d,2H,J=5 Hz, CH2Ar).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
Add nitric acid (65%, 21.0 g, 0.22 mol) dropwise to a cooled mixture (−10° C.) of (2-bromo-4-fluorophenyl)acetic acid (50 g, 0.22 mol) in concentrated sulfuric acid (250 mL) and stir the resulting mixture at −10-0° C. for 20 min. Pour onto crushed ice, extract with EtOAc (3×200 mL), wash organics with brine (3×100 mL), dry over sodium sulfate, and concentrate in vacuo to give the title compound (50 g, 84% yield). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J=7.6 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 3.87 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)#[N:2].C(O)(=[O:30])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)[CH:6]=[C:7]2[C:8]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]2=1)(=[O:30])[NH2:2]
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccc(Nc3ccc(C(=O)O)cc3)c(C#N)c2)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)O)cc4c3c2)cc1F
Temperature: 130 °C

Procedure:
A 350 ml pressure flask was loaded with 4-(3-cyano-3′-fluoro-4′-methoxybiphenyl-4-ylamino)benzoic acid (4.52 g, 9.73 mmol), acetic Acid (200 mL) and palladium(II) acetate (4.37 g, 19.46 mmol), sealed and heated to 130° C. for 12 hours. The mixture was filtered through CELITE®, the solids washed with acetic acid and the collected filtrate concentrated in vacuum. 2.14 g brown solid 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-3-carboxylic acid were isolated and used without further purification. HPLC retention time 9.26 min (HPLC conditions as in Table 9 and Table 10). MS (ESI) m/z [M−H]− 477.
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:22])[N:10]=[C:11]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.N(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[I:22][C:9]1[N:10]=[C:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]2)[N:4]2[C:5]=1[C:6](=[O:8])[NH:7][CH:2]=[N:3]2
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]c(N)nn32)CC1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl trans-4-(2-amino-5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.880 g, 0.00211 mol) in anhydrous THF (74 mid) and DMF (13.2 mL) was charged with tert-butyl nitrite (1.2 mL, 0.010 mol) and stirred at rt for 2 h. The reaction was concentrated in vacuo and was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 570 mg, (67% yield) of the title compound as a pale orange solid. (1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.54 (m, 2H), 1.56-1.69 (m, 2H), 1.92-2.06 (m, 4H), 2.36-2.46 (m, 1H), 3.02-3.14 (m, 1H), 3.61 (s, 3H), 7.89 (d, J=3.28 Hz, 1H) and 11.79 (br. s., 1H); MS (ES+): m/z 402.86 [MH+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH2:37][OH:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH2:37][OH:38])[C:25](=[O:26])[CH2:24][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: OCCNCc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCO)Cc2ccccc2)c2ccc3cn[nH]c3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18]O)[C:13](=[O:20])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:21]1([N:27]2[C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:30](=[O:37])[NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:6][C:7]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][N:34]3[CH2:33][CH2:32][C:31]4([N:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:28][NH:29][C:30]4=[O:37])[CH2:36][CH2:35]3)[C:13](=[O:20])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=c1[nH]c2cccc(Cl)c2n1CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cccc(Cl)c31)CC2
Yield: 17 %

Procedure:
A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.5 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized twice from a mixture of N,N-dimethylformamide and water, yielding 0.8 parts (17%) of 8-[3-(7-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 258.4° C.