Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C2C(Cl)=CN=C(N[C@H]3CC[C@H](N[CH2:31][C@H:32]([OH:37])[C:33]([F:36])([F:35])[F:34])CC3)C=2)=NC(NCC2CCOCC2)=CC=1.[NH2:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([NH:45][C:46]2[CH:51]=[C:50]([C:52]3[C:57]([Cl:58])=[CH:56][CH:55]=[C:54]([NH:59][CH2:60][CH:61]4[CH2:66][CH2:65][O:64][C:63]([CH3:68])([CH3:67])[CH2:62]4)[N:53]=3)[C:49]([Cl:69])=[CH:48][N:47]=2)[CH2:41][CH2:40]1.FC(F)(F)[C@H]1OC1>CC(O)C>[Cl:58][C:57]1[C:52]([C:50]2[C:49]([Cl:69])=[CH:48][N:47]=[C:46]([NH:45][C@H:42]3[CH2:43][CH2:44][C@H:39]([NH:38][CH2:31][C@H:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[CH2:40][CH2:41]3)[CH:51]=2)=[N:53][C:54]([NH:59][CH2:60][CH:61]2[CH2:66][CH2:65][O:64][C:63]([CH3:67])([CH3:68])[CH2:62]2)=[CH:55][CH:56]=1
Reactant: O[C@@H](CN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1)C(F)(F)F
Reactant: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)CCO1
Agent: FC(F)(F)[C@@H]1CO1
Solvent: CC(C)O
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](NC[C@H](O)C(F)(F)F)CC4)ncc3Cl)n2)CCO1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Preparation of (S)-3-(trans-4-(3,5′-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol: To a solution of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (19 mg, 0.040 mmol) in 2-propanol (0.3 mL) was added (S)-(−)-3,3,3-trifluoro-1,2-epoxypropane (3.4 uL, 0.040 mmol). The mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 9.1 mg of (2S)-3-(trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol as its TFA salt. LCMS (m/z): 590.5 (MH+), retention time=0.71 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81-1.32 (m, 12 H) 1.33-1.66 (m, 4 H) 1.82-1.99 (m, 1 H) 1.99-2.21 (m, 4 H) 2.89-3.04 (m, 2 H) 3.04-3.19 (m, 2 H) 3.27 (d, J=2.35 Hz, 2 H) 4.40 (br. s., 1 H) 6.38 (s, 1 H) 6.55 (d, J=9.00 Hz, 1 H) 6.77 (br. s., 1 H) 6.91 (br. s., 1 H) 7.21 (br. s., 1 H) 7.48 (d, J=9.00 Hz, 1 H) 8.03 (s, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.S(O)(O)(=O)=O.CS[C:19](=[NH:21])[NH2:20].C(NC1N=C(C2C(C(C)C)=NN3C=CC=CC=23)C=CN=1)(C)C>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:19]([NH2:21])=[NH:20])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CSC(=N)N
Agent: CC(C)Nc1nccc(-c2c(C(C)C)nn3ccccc23)n1
Agent: O=S(=O)(O)O
Product: CN1CCN(CCCNC(=N)N)CC1

Procedure:
N-[3-(4-Methyl-piperazin-1-yl)-propyl]-guanidine was prepared from 3-(4-methyl-piperazin-1-yl)-propylamine and 2-methyl-2-thiopseudourea sulfate following the method used in Step 3 of the synthesis of Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine (Example 66). LC/MS 200.2 m/z (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[C:5]([C:11]#[N:12])=[C:4]([OH:13])[C:3]=1[CH3:14].[CH3:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1>CC(O)C.C(OCC)(=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[C:5]([C:11]#[N:12])=[C:4]([OH:13])[C:3]=2[CH3:14])=[CH:22][CH:23]=1)[CH3:15]
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1c(O)c(C#N)c2ccnn2c1Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOc1ccc(Nc2c(C)c(O)c(C#N)c3ccnn23)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
The crude product (9.25 mg) of 7-chloro-5-hydroxy-6-methylpyrazolo[1,5-a]pyridine-4-carbonitrile (13) was dissolved in 2-propanol (2.2 mL). To this solution, p-phenetidine (289 μL) was added and the mixture was stirred under reflux with heating for 3 days. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. This solution was washed with a mixture of brine and 1 mol/L hydrochloric acid (1:1) and then with a mixture of brine and saturated aqueous sodium hydrogen carbonate solution (9:1) and dried over sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified with silica-gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (21) (77.8 mg, Yield 56%).
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[OH:15][C@H:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>CC(O)C>[OH:15][C@H:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18].[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Clc1cc(Cl)cc(C2CCNC2)c1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: Clc1cc(Cl)cc([C@H]2CCNC2)c1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 17.7 %

Procedure:
3-(3,5-dichlorophenyl)pyrrolidine oxalate (471.6 g, 1.54 mol) was dissolved in 2 M aqueous NaOH solution (1000 mL) and extracted with ethyl acetate (3×350 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to provide the free base of (R)-3-(3,5-dichlorophenyl)pyrrolidine (325.4 g, 98%) as a clear amber oil. A 5 L round bottom flask was fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe/controller, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged with 3-(3,5-dichlorophenyl)pyrrolidine (100 g, 0.46 mol) and 2-propanol (800 mL, 8 mL/g) under a nitrogen atmosphere at RT. (2R)-2-hydroxy-2-phenylacetic acid (70.4 g, 0.46 mol) was added as a solid in one portion, and the resulting solution was stirred for 5 min when a solid began to form. The suspension was heated at 85° C. for 5 min and then allowed to slowly cool to RT. The solid was filtered, washed with 2-propanol (2×250 mL) and dried under high vacuum. Repeated recrystallization of this salt (8×) in 2-propanol (1 mL/g) afforded (R)-3-(3,5-dichlorophenyl)pyrrolidine (R)-2-hydroxy-2-phenylacetate (30 g, 18%) in >96% ee. Absolute configuration was assigned based on X-ray analysis. 1H-NMR (400 MHz, DMSO-d6) δ 7.50 (t, J=1.8 Hz, 1H), 7.42-7.38 (m, 5H), 7.26-7.22 (m, 2H), 7.16 (dd, J=5.2, 9.3 Hz, 1H), 4.61 (s, 1H), 3.51 (dd, J=8.2, 10.9 Hz, 1H), 3.44-3.27 (m, 2H), 3.15-3.01 (m, 3H), 2.50 (t, J=1.8 Hz, 1H), 2.32-2.24 (m, 1H) and 1.91-1.81 (m, 1H) ppm. Chiral HPLC (Astec Chirobiotic, (25 cm×4.6 mm), 100% MeOH (0.1% TEA, 0.1% HOAc), 1.2 mL/min): tR=33.9 min (S), 34.9 min. (R).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[CH:22]=[O:23])[N:15]=2)[NH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[O-:33]Cl=O.[Na+]>CC(O)(C)C>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[C:22]([OH:33])=[O:23])[N:15]=2)[NH:10][C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-methoxybenzaldehyde (296 mg, 0.82 mmol) in t-BuOH (18.2 mL) was sequentially added saturated aqueous NaH2PO4 solution (4.1 mL), 2-methyl-2-butene (2M in THF, 3.92 mL) and NaClO2 (114.8 mg). The mixture was stirred at room temperature for one hour, and then concentrated under reduced pressure. The residue thus obtained was purified by column chromatography [silica gel; MeOH/DCM (1:9)] to give the product as white powder (244 mg, 65%). 1H NMR (400 MHz, DMSO): δ 8.44 (s, 1H), 8.19 (s, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.40-7.26 (m, 5H), 7.18 (d, J=8.8 Hz, 1H), 5.05 (s, 2H), 3.84 (s, 3H). MS: 377.0 (M+H).
Reaction SMILES: B(F)(F)F.CCO[CH2:8][CH3:9].C(=O)C1OC=CC=1.[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26])=[CH2:18].C1(=O)C=CC(=O)C=C1>>[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26])=[CH2:18].[C:8]1([CH3:9])[CH2:23][CH2:24][CH:19]([C:20]([CH3:25])=[CH2:21])[CH2:17][CH:18]=1
Reactant: CCOCC
Agent: C=Cc1ccccc1C=C
Agent: FB(F)F
Agent: O=C1C=CC(=O)C=C1
Solvent: O=Cc1ccco1
Product: C=C(C)C1CC=C(C)CC1
Yield: 10 %

Procedure:
Many other additives were examined in the BF3.OEt2-catalyzed polymerization reactions of the Norway fish oil (Table 16). The copolymerization of furfural, divinylbenzene, and the Norway fish oil produced very hard, dark-colored thermosets in excellent overall mass recoveries (entries 2-4). Interestingly, p-benzoquinone and divinylbenzene polymerized with the Norway fish oil violently at room temperature to produce dark-colored polymeric materials (entries 7-10). The most interesting material was produced when 20% divinylbenzene and 10% p-mentha-1,8-diene were polymerized with the Norway fish oil using 5 weight percent BF3.OEt2 (entry 11). This reaction produced a very hard, shiny, dark-brown thermoset after being heated at 60° C. for one day and then 110° C. for 2 days. Furan and divinylbenzene were copolymerized with the Norway fish oil to produce very firm, dark-colored thermosets that were resistant to applied pressure (entries 13, 14).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH3:36])[CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CN(C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-morpholine dihydrochloride (0.067 mmol, 0.031 g) and aqueous formaldehyde (37%, 0.304 mmol, 0.025 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.364 mmol, 0.154 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methyl-morpholine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.022 g). LCMS: m/z 441 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.35-7.46 (3H, m), 7.09 (2H, d), 4.56-4.68 (2H, m), 4.38-4.47 (1H, m), 4.13-4.29 (2H, m), 3.91 (1H, t), 3.68 (1H, d), 3.49 (1H, d), 3.12-3.26 (2H, m), 3.00-3.09 (2H, m), 2.97 (3H, s), 1.99-2.02 (2H, m), 1.80-1.82 (2H, m), 1.19-1.66 (10H, m), 0.81 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][O:9]C2C=CC(C3CCN(C4C=CC5N(C(C(F)(F)F)=NN=5)N=4)CC3)=CC=2)=[CH:5][CH:4]=[N:3]1.C([Li])CCC.CN1C=CC=N1.O1CC1>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: Cn1cccn1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CO1
Product: Cn1nccc1CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The 2-(1-methyl-1H-pyrazol-5-yl)ethanol used as starting material was prepared as follows:—n-Butyl lithium (1.6M in hexanes) (1226 mL, 1961.78 mmol) was added dropwise to 1-methyl-1H-pyrazole (153.4 g, 1868.37 mmol) in THF (3000 mL) cooled to −78° C. over a period of 1 hour under nitrogen. The resulting solution was stirred at −60° C. for 30 minutes, then warmed to −10° C. and stirred for a further 40 minutes. A solution of oxirane (210 mL, 4203.82 mmol) in THF (600 mL) was added slowly at −10° C. followed by further THF (1000 mL) and the resulting slurry was stirred at −10° C. for 30 minutes, then at 0° C. for 30 minutes. The mixture was then allowed to gradually warm to room temp under nitrogen and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution (2000 ml), the layers separated and the aqueous phase extracted with n-butanol (3×1000 ml). The combined organics were washed with saturated brine (1500 ml), dried over MgSO4, filtered and evaporated to give an oil, which was azeotroped with toluene (1000 ml) to leave an oil with some solid. The oil was dissolved in DCM and the insoluble solid was filtered off and washed with DCM. The filtrate was purified by chromatography using a silica Novasep prep HPLC column, eluting with a gradient of 5-10% methanol in DCM. Pure fractions were evaporated to dryness to afford 2-(1-methyl-1H-pyrazol-5-yl)ethanol (195 g, 83%) as an oil.
Reaction SMILES: [C:1]([C@:3]1([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=C(OC)C=2OC)[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1N=[N+]=[N-])#[CH:2].[F:45]C(F)(F)C(O)=O.[OH-].[NH4+]>C(Cl)Cl>[C:1]([C@:3]1([CH2:20][OH:21])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[F:45])#[CH:2]
Reactant: C#C[C@]1(COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: O=C(O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: C#C[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F

Procedure:
A solution of 4′-C-ethynyl-5′-O-(dimethoxytrityl)-3′-fluoro-3′-deoxythymidine (12, X═F) (1 mmol) in a solution of 1% trifluoroacetic acid in methylene chloride (20 mL) is stirred at room temperature for 3 h and neutralized with ammonium hydroxide. Solvent is evaporated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (2-5% MeOH in methylene chloride) to give 4′-C-ethynyl-FLT (Ia, X═F).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].CC1(C)COB([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=2)OC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:3]1[C:2]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=2)=[C:10]([F:11])[CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[O:13])=[CH:6][NH:7]2
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Reactant: CC1(C)COB(c2ccc(OCCCO)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(OCCCO)cc3)c(F)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
To the slurry of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde was added 2 M potassium carbonate (0.7 mL) and the mixture was stirred at room temperature for 5 min. Then 3-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)propan-1-ol (120 mg, 0.46 mmol) and Pd(dppf)Cl2 (20 mg) was added to the reaction. The reaction was heated to 90° C. for 30 min. Solvent was removed under reduced pressure to give a residue, which was purified by silica gel chromatography (petroleum ether/ethyl acetate=4:1) to give the title compound (30 mg, 20%) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:33]=O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([CH2:33][N:4]3[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]4[CH2:19][C:18]5[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=5[CH2:12][CH2:11]4)[CH2:2][CH2:3]3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: CCCN(CCN1CCN(Cc2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(O)cc2C1
Yield: 32.5 %

Procedure:
Compound 40b was prepared according to Procedure A using 39a (65 mg, 0.20 mmol) and indole-5-carboxaldehyde (35 mg, 0.24 mmol) to give 40b (29 mg, 32%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.84 (t, 3H, J=7.2 Hz), 1.33-1.44 (m, 3H), 1.85 (d, 1H, J=10.0 Hz), 2.41-2.82 (m, 19H), 3.60 (s, 2H), 6.35 (d, 1H, J=2.0 Hz), 6.49-6.58 (m, 2H), 6.85 (d, 1H, J=8.4 Hz), 7.14-7.20 (m, 2H), 7.31 (d, 1H, J=8.4 Hz), 7.54 (s, 1H), 8.38 (bs, 1H). The free base of 40b was converted into oxalate salt. m.p. 198-203° C. Anal. [C28H38N4O.2.5(COOH)2.3H2O]C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>O.C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)nc1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccc(F)cc2)nc1
Yield: 45.8 %

Procedure:
A mixture of 0.70 g (2.8 mmol) of 2-(4-fluoro-benzyloxy)-5-nitro-pyridine and 2.36 g (4.2 mmol) of iron powder in 35 ml of water and 0.7 ml of acetic acid is heated under reflux for 4 hours. For the working-up, the reaction mixture is treated under vigorous stirring with water and ethyl acetate, thereafter, filtered over a layer of Dicalit. The organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure. There are obtained 0.28 g (45% of theory) of 6-(4-fluoro-benzyloxy)-pyridin-3-ylamine as a greenish solid which is engaged in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:7]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: Fc1ccc(I)cc1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 87.6 %

Procedure:
Sequentially add 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol), (bis(triphenylphosphine)palladium (II) dichloride (69 mg, 0.10 mmol), and copper (I) iodide (38 mg, 0.198 mmol) to a solution of 1-fluoro-4-iodo-2-trifluoromethylbenzene (575 mg, 1.98 mmol) in triethylamine (4 mL) under nitrogen. Heat at 70° C. for 2.5 h and concentrate. Purify the residue by silica gel chromatography, eluting from 0:100 to 20:80 using ethyl acetate:hexanes, to give the title compound as a white solid (520 mg, 88%).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:54])[C:26]([C:29]1[CH:34]=[CH:33][C:32](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27].C(NCC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:54])[C:26]([C:29]1[CH:30]=[CH:31][C:32]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:33][CH:34]=1)([CH3:28])[CH3:27]
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.082 g, 0.27 mol), diethyl amine (2 mol), copper(I)iodide (0.020 g, 0.1 mol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound was obtained as a brown oil (0.040 g, 31%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]([O:17]CC)=O)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:20]1([C:23](=[N:25]O)[NH2:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[N:25]=[C:15]([C:14]3[N:13]=[CH:12][N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:11]=[C:2]([CH3:1])[C:3]=34)[O:17][N:24]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ncn2c1c(C)nc1ccccc12
Reactant: NC(=NO)C1CC1
Product: Cc1nc2ccccc2n2cnc(-c3nc(C4CC4)no3)c12

Procedure:
M.p. 188°-189° C., from ethyl 4-methylimidazo[1,5-a]quinoxaline-3-carboxylate and cyclopropancarboxamide oxime. (Compound 10)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O1CCOCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]3([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C1(CC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)CCCC1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentanecarboxylate (1.58 g, 4.64 mmol), 4-nitro phenyl boronic acid (0.93 g, 5.6 mmol), toluene (45 mL), and dioxane (13 mL), followed by the addition of a saturated aqueous sodium carbonate solution (13 mL). The mixture was degassed using argon and 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.19 g, 0.23 mmol) was added, followed by an additional 15 minutes of degassing, and the deep red reaction mixture was heated to 85° C. for 16 h. The very darkly colored reaction mixture was allowed to cool, and then was diluted with ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and filtered under reduced pressure through 2 cm Celite®2 cm silica. The filtrate was concentrated under reduced pressure, leaving a dark red-brown oil, that was purified by flash chromatography (4:1/hexane:ethyl acetate, then 3:1/hexane:ethyl acetate, then 2:1/hexane:ethyl acetate) to afford methyl 1-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate (1.65 g, 93%). LC-MS ret. time 3.56 min, m/z 368.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.56-1.85 (overlapping signals, 6H), 2.23-2.37 (m, 2H), 3.45 (s, 2H), 3.67 (s, 3H), 7.70 (d, 2H), 7.77 (d, 2H), 8.06 (d, 2H), 8.34 (d, 2H).