Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].[C:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[N:9]=[C:8]([C:32]2[CH:33]=[C:28]([NH:27][C:24](=[O:26])[CH3:25])[CH:29]=[CH:30][CH:31]=2)[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Cl)nc1Cl
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(-c2cc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c(Cl)n2)c1
Temperature: 90 °C
Yield: 42.7 %

Procedure:
A mixture of 2,6-dichloro-4-(4-phenoxyphenyl)nicotinonitrile (51 mg, 0.149 mmol, from Step 2 of Example 8), 3-acetamidophenylboronic acid (29.4 mg, 0.164 mmol), palladium tetrakis(triphenylphosphine) (15.12 mg, 0.015 mmol) and potassium phosphate tribasic monohydrate (0.299 mL, 0.598 mmol) in N,N-dimethylformamide (1.5 mL) was heated to 90° C. under nitrogen for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (80 mL), washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 5-40% ethyl acetate in hexanes, gave N-(3-(6-chloro-5-cyano-4-(4-phenoxyphenyl)pyridin-2-yl)phenyl)acetamide as white solid (28 mg, 42% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (1H, s), 7.79-7.89 (1H, m), 7.77 (1H, s), 7.67-7.73 (1H, m), 7.58-7.66 (2H, m), 7.50-7.57 (1H, m), 7.37-7.47 (3H, m), 7.17-7.24 (1H, m), 7.05-7.16 (4H, m), 2.22 (3H, s); MS (ES+) m/z: 440 (M±H); LC retention time: 4.165 min (analytical HPLC Method A).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc3ccccc23)cc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)Nc2cccc3ccccc23)cc1O
Reaction time: 0.67 h

Procedure:
A suspension of (E)-3-(3-acetoxy-4-methoxy-phenyl)-N-naphthalen-1-yl-acrylamide (254 mg, 0.70 mmol) in a mixture of MeOH (4.5 mL) and 50%w/w aqueous NaOH (74 μL) was heated under stirring for 40 min at the reflux temperature. The mixture was then concentrated under reduced pressure to give a light yellow oil that was taken up and triturated with 4 mL of aqueous HCl 0.5N. After filtration and drying 213 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-naphthalen-1-yl-acrylamide were obtained as a white powder.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[CH2:15]([N:18]([CH2:29][CH:30]=[CH2:31])[C:19]1[N:23]2[CH:24]=[C:25](F)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1)[CH:16]=[CH2:17]>CN(C=O)C>[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:25]2[CH:26]=[CH:27][C:22]3[N:23]([C:19]([N:18](/[CH:29]=[CH:30]/[CH3:31])/[CH:15]=[CH:16]/[CH3:17])=[N:20][N:21]=3)[CH:24]=2)[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: C=CCN(CC=C)c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/N(/C=C/C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
To a suspension of sodium hydride (40% in mineral oil, 690 mg, 17.31 mmol) in DMF (20 mL) was added Intermediate A (1.12 g, 6.92 mmol) and the reaction mixture was stirred for 20 min at RT. A solution of Intermediate 101b (1.34 g, 5.77 mmol) in DMF (20 mL) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched by careful addition of MeOH and then loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.33 g, 61%) as an orange gum. 1H NMR (400 MHz, CDCl3): 0.92-1.13 (1H, m), 1.39 (6H, dd, J=7.2, 1.7 Hz), 1.82-2.16 (4H, m), 2.26-2.38 (1H, m), 3.93-3.99 (1H, m), 4.99-5.10 (2H, m), 5.18 (1H, t, J=4.4 Hz), 6.10 (2H, dd, J=8.2, 2.0 Hz), 7.09 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.44 (3H, m), 7.48-7.53 (1H, m), 7.57-7.66 (2H, m).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([F:17])[F:16])[CH:12]=3)[C:7]([C:18]#[N:19])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:18]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH:15]([F:16])[F:17])=[CH:10][CH:9]=2)[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]=1[B:20]([OH:25])[OH:21])#[N:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cn(C2CCC2)c2cc(OC(F)F)ccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)n(C2CCC2)c2cc(OC(F)F)ccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 1-cyclobutyl-6-(difluoromethoxy)-1H-indole-3-carbonitrile (1.5 g, 5.7 mmol) and triisopropyl borate (2.4 mL, 10.3 mmol) in THF (25 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 5.0 mL, 7.5 mmol). The mixture was stirred at −78° C. for 30 min and then quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with 2 N aq. HCl to pH 5 and extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-cyano-1-cyclobutyl-6-(difluoromethoxy)-1H-indol-2-ylboronic acid as a solid (1.8 g, 60% pure by LCMS) that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl.O1CCOCC1>CO.O.CC(OC)(C)C.Cl[Pd]Cl.C(Cl)Cl>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
Methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 4-(trifluoromethyl)phenylboronic acid (8.30 g, 43.71 mmol), potassium carbonate (6.04 g, 43.71 mmol) and PdCl2 (dppf) (0.633 g, 0.87 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. Two drops of water were added to one of the vials and the vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude was dissolved in MTBE (180 mL) and solids filtered off. Hydrogen chloride (4 M in dioxane, (7.29 mL, 29.14 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 2.5 h. The solid was collected by filtration and washed with MTBE. MTBE and satd NaHCO3 was added to the solid, the organic phase dried (Na2SO4), filtered and evaporated to yield methyl 2-(4-(trifluoromethyl)phenyl)isonicotinate (5.75 g, 70%) as a beige solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 7.75 (d, 2H), 7.84 (dd, 1H), 8.18 (d, 2H), 8.33 (s, 1H), 8.87 (dd, 1H). MS m/z 282 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:28]I>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CI
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N(C)S(C)(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (194 mg) described in Example 461 and methyl iodide (34 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (57 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[N+:29](C1C=C2C(=CC=1)C(=O)NC(=O)C2)([O-:31])=[O:30].CN1CCN(CC2C=CC(N)=CC=2)CC1.C(OCC)(OCC)OCC>C(O)CO>[N+:29]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([O-:31])=[O:30]
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1
Agent: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CCOC(OCC)OCC
Solvent: OCCO
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc([N+](=O)[O-])cc43)cc2)CC1
Yield: 32 %

Procedure:
Using the procedure described for (4Z)-6-bromo-4-({[4-(4-methylpiperazin-1-yl)phenyl}amino}methylene)isoquinoline-1,3(2H,4H)-dione (Example 27), 0.21 g (1.0 mmol) of 6-nitroisoquinoline-1,3(2H,4H)-dione, 0.20 g of 4-(4-methylpiperazin-1-yl)methyl-phenylamine, 0.18 ml (1.1 mmol) of triethyl orthoformate, and 2.0 ml of ethylene glycol were reacted to give 0.13 g (32%) of amber solid, mp 250-2600 (dec); MS (ES+) m/z 408.2 (M+H)+1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([CH3:24])[C:20]=3[NH2:25])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2].Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([CH3:24])[C:20]=3[NH:25][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:29]=3)=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3Nc3cccc(-c4ccccc4)n3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 3-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-propionic acid ethyl ester and 2-bromo-6-phenyl-pyridine. Additionally, palladium(II) acetate was used as the catalyst in place of tris(dibenzylideneacetone)dipalladium(0).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.CCCC(C)C>CN(C=O)C.CCOC(C)=O.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C@@H:2]2[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 11.6 mmol) in DMF (3 ml) was added in one portion to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 490 mg, 12.2 mmol) in DMF (15 mL) at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 10 mins and then warmed to room temperature and stirred for 20 mins and then a solution of 1-fluoro-4-nitrobenzene (1.24 mL, 11.6 mmol) in DMF (2 mL) was added in one portion. The reaction mixture was stirred at room temperature for 2 h and then heated at 110° C. for 24 h. The solution was concentrated in vacuo to leave a residue that was taken up in EtOAc (250 mL) and H2O (150 mL) was added. The layers were separated and the organic layer was washed with H2O (2×100 mL) and brine (50 mL) and then dried (MgSO4) and concentrated in vacuo to leave an oil. The oil was taken up in a mixture of hot EtOAc and isohexane (1:1) and left for 20 h. Filtration, followed by concentration in vacuo of the filtrate left an oil, which was purified by column chromatography, using a gradient of 10-40% EtOAc:isohexane as eluent, to give the title compound (0.27 g, 16%) as an oil; 1H NMR (CDCl3) δ 1.24 (3H, q), 1.66-1.72 (2H, m), 1.74-1.79 (2H, m), 1.90-1.95 (2H, m), 1.98-2.04 (2H, m), 2.38-2.44 (1H, m), 4.11-4.16 (2H, q), 4.57-4.60 (1H, m), 6.90-6.93 (2H, d), 8.15-8.18 (2H, d).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38](=[O:40])[NH2:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:42])[CH3:41])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:25]([C:23]2[O:24][C:20]([C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:41])([CH3:42])[CH2:10]4)=[CH:19][CH:18]=3)=[C:21]([C:38]([NH2:39])=[O:40])[N:22]=2)=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(N)=O)cc2)CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(N)=O)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-{4-[4-Carbamoyl-2-(7-trifluoromethyl-1H-indol-4-yl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g crude) was dissolved in a mixture of DCM and TFA (30 mL 2:1), and the solution was stirred at RT for 2 hrs, when the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo to give the crude product which was purified by prep-HPLC to give the title compound (60 mg, 41% from ethyl 5-(4-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)phenyl)-2-iodooxazole-4-carboxylate).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OCC)=[O:11].[H-].[Na+].Cl>O1CCCC1>[O:11]=[CH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C=O)c1ccccc1
Temperature: 50 °C

Procedure:
3-Oxo-2-phenylpropanenitrile was prepared by addition of a mixture of phenylacetonitrile (0.90 g, 7.68 mmol) and ethyl formate (0.85 g, 11.5 mmol) dropwise to a stirred suspension of sodium hydride (0.41 g of 60%, 10 mmol) in tetrahydrofuran (4.5 mL). Reaction was rapid and exothermic. After heating in an oil bath at 50° C. for 20 min., the mixture was carefully acidified with dilute HCl and extracted with ethyl acetate. Extracts were washed with water, saturated NaCl solution, dried (MgSO4) and stripped to give 0.96 g (86%) of off-white solid, m.p. 148-153° C., Rf 0.5 (silica gel, ethanol:ethyl acetate:hexane=1:4:4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCC#Cc1ncccn1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCc1ncccn1
Yield: 29.4 %

Procedure:
A solution of 6-(2-pyrimidinyl)-5-hexynol (3.09 g) in ethanol (100 ml) was added to a pre-hydrogenated suspension of 10% palladium on charcoal (1.05 g) in ethanol (50 ml) and hydrogenated at room temperature and pressure, filtered and evaporated in vacuo. The residual oil was purified by FCC eluting with ether and System C (99:1-85:15) to give the title compound as a pale yellow oil (0.93 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[N:15]([CH:16]=1)[CH2:14][C:13]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=1[NH:11][C:10]2=O>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]2[N:15]([CH:16]=1)[CH2:14][C:13]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=1[N:11]=[C:10]2[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccc(Cl)cc2Cn2cc(Cl)cc21
Solvent: ClC(Cl)Cl
Product: ClC1=Nc2ccc(Cl)cc2Cn2cc(Cl)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Add phosphoryl chloride (5 equiv; 4.36 mL, 7.19 g, 46.89 mmoles) to 2,7-dichloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1 equiv; 2.505 g, 9.38 mmoles) in chloroform (80 mL) and heat and stir at 50° C. overnight. Decant the reaction solution and evaporate in vacuo to an oil. Dissolve the oil in DCM, wash with saturated aqueous sodium hydrogen carbonate solution. Dry the DCM solution over Na2SO4, filter and concentrate to dryness to give 2,7,11-trichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as a cream colored solid. In parallel desalt methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate hydrochloride (0.837 g, 3.54 mmoles) by dissolving in methanol, add the methanolic solution to an SCX-2 column (10 g) wash with methanol and then elute with 2.5M ammonia in methanol solution, evaporate the methanol ammonia fraction to give methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate (0.665 g) as an oil. Mix this oil with 2,7,11-trichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.505 g 1.77 mmoles), potassium carbonate (0.733 g, 5.31 mmoles) and acetonitrile (20 mL) and heat at reflux overnight. Cool the reaction mixture to room temperature and filter, washing the sinter with EtOAc, then evaporate the filtrate in vacuo to a solid. Chromatograph on silica eluting with methanol/DCM (gradient elution 2:98 to 8:92). Evaporate the fractions containing product to give methyl 3-[4-(2,7-dichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (0.69 g). MS (m/z): 449.13/451.07 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:11]([C:13]1[CH:31]=[CH:30][C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([CH:28]=2)[C:25](Cl)=[O:26])=[O:18])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:30]=[CH:31][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH:21]=[CH:22][C:23]=2[CH3:29])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1C(=O)Cl
Reactant: CCCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(NC(=O)c2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Yield: 16.4 %

Procedure:
4-n-Propylaniline (0.11 g) was added to a stirred suspension of 5-(4-cyanobenzamido)-2-methylbenzoyl chloride (0.224 g), triethylamine (0.21 ml) and methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.049 g); NMR Spectrum: (DMSOd6) 0.87 (t, 3H), 1.56 (m, 2H), 2.33 (s, 3H), 2.48 (m, 2H), 7.13 (d, 2H), 7.28 (d, 1H), 7.63 (m, 2H), 7.83 (m, 3H), 8.01 (d, 1H), 8.1 (m, 2H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:26])[C:20]=3[NH:19][C:18]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:17]2=3)=[O:15])[CH2:10][CH2:9]1>ClCCl.C(N(CC)CC)C>[CH3:26][N:21]1[C:20]2[NH:19][C:18]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:17]=3[N:16]([C:14]([CH:11]3[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:9][CH2:10]3)=[O:15])[CH2:25][C:24]=2[CH:23]=[N:22]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CN)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=432.1
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O.C(O)(CC)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CS(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]=1[C:65]1[CH:70]=[C:69]([N:71]2[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]2=[O:78])[CH:68]=[C:67]([C:79]([CH3:82])([CH3:81])[CH3:80])[C:66]=1[O:83][CH3:84])(=O)=O.[CH3:85][S:86]([NH2:89])(=[O:88])=[O:87]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:79]([C:67]1[C:66]([O:83][CH3:84])=[C:65]([C:56]2[CH:57]=[C:62]3[C:63](=[CH:64][CH:55]=2)[CH:58]=[C:59]([NH:89][S:86]([CH3:85])(=[O:88])=[O:87])[CH:60]=[CH:61]3)[CH:70]=[C:69]([N:71]2[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]2=[O:78])[CH:68]=1)([CH3:80])([CH3:82])[CH3:81]
Reactant: CS(N)(=O)=O
Reactant: COc1c(-c2c(OS(C)(=O)=O)ccc3ccccc23)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: O
Solvent: CCC(C)(C)O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.0018 g, 8.09 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0086 g, 0.018 mmol) and water (0.6 μ, 0.032 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, and the contents were heated to 80 ° C. and stirred at this temperature for 15 minutes. The reaction mixture was cooled down to room temperature. Potassium phosphate tribasic (0.094 g, 0.445 mmol), 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenylnapthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to the 40-mL reaction vial. The reaction temperature was raised to 110 ° C. and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 5 area % at 210 nm.