Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].O1CCOCC1.O>[NH2:46][C:33]1[N:32]=[C:31]([O:30][CH3:29])[C:36]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]3[CH:10]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:11]([C:14]4[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=4[CH3:21])[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:35][N:34]=1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(N)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C

Procedure:
A degassed mixture of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate B) (0.314 mmol), 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate U) (0.627 mmol), PdCl2(dppf).CH2Cl2 adduct (0.047 mmol) and K3PO4 (1.255 mmol) in 3:1 dioxane/H2O (4 mL) was heated at 100° C. for 30 min. After cooling to rt, the reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were washed successively with H2O and brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (prep-HPLC 1) and then triturated in Et2O to afford the title compound as a white solid. ESI-MS: tR=1.21 min, [M+H]+ 522/524/526 (LC-MS 1); 1H-NMR (d6-DMSO, 600 MHz): 7.93 (s, 1H), 7.76 (s, 1H), 7.37 (m, 2H), 7.24 (m, 2H), 7.14 (m, 1H), 7.10 (m, 1H), 6.89 (s, 2H), 6.47 (s, 1H), 6.22 (s, 1H), 3.94 (m, 1H), 3.80 (s, 3H), 1.92 (s, 3H), 1.29 (m, 3H), 0.49 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2ccccc2)c2c1C(=O)NC2
Yield: 88.8 %

Procedure:
In a similar manner to Step 2 of Example 1, 7-amino-4-bromoisoindolinone (250 mg, 1.10 mmol) was dissolved in acetonitrile (15 mL), and the solution was treated with phenylboronic acid (402 mg, 3.30 mmol), palladium acetate (20 mg, 0.088 mmol), tri(o-tolyl)phosphine (53.6 mg, 0.176 mmol) and triethylamine (1.53 mL, 11.0 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1, chloroform/acetonitrile=6/1) to obtain 7-amino-4-phenylisoindolinone (219 mg, yield 89%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]([O:15]C(C)(C)C)=O)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C:3]1=[O:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:31][NH:32][CH3:33].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH3:33][N:32]([CH2:31][C:23]1[N:22]([CH3:21])[C:30]2[C:25]([CH:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH2:4][C:3](=[O:20])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1)=[O:15]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2NCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN1Cc2cc(C(=O)N(C)Cc3cc4ccccc4n3C)ccc2NCC1=O
Yield: 91.8 %

Procedure:
According to the procedure of Example 8, except using tert-butyl 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.60 g, 2.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.35 g, 2.2 mmole), Et3N (0.62 mL, 4.4 mmole), HOBt.H2O (0.30 g, 2.2 mmole), and EDC.HCl (0.42 g, 2.2 mmole), the title compound (0.76 g, 92%) was prepared as an off-white solid following flash chromatography on silica gel (5% MeOH/CHCl3): MS (ES) m/e 377.0 (M+H)+.
Reaction SMILES: C([C:3]1[C:4](=[O:13])[NH:5][C:6]([CH2:11][CH3:12])=[CH:7][C:8]=1[CH2:9][CH3:10])#N.C(CC(=O)CC)(=O)CC.C(CC(N)=O)#N.C(NCC)C.Cl>C(O)C>[CH2:9]([C:8]1[CH:7]=[C:6]([CH2:11][CH3:12])[NH:5][C:4](=[O:13])[CH:3]=1)[CH3:10]
Reactant: CCc1cc(CC)c(C#N)c(=O)[nH]1
Agent: CCC(=O)CC(=O)CC
Agent: Cl
Agent: N#CCC(N)=O
Solvent: CCNCC
Solvent: CCO
Product: CCc1cc(CC)[nH]c(=O)c1

Procedure:
Basu [J. Indian Chem. Soc. 7, 815 (822-3) (1930)] describes the preparation of 3-cyano-4,6-diethyl-2(1H)-pyridinone (p. 822, VI) by reacting dipropionylmethane with cyanoacetamide in ethanol in the presence of diethylamine. In this same paper Basu heated 3-cyano-4,6-diethyl-2(1H)-pyridinone with concentrated hydrochloric acid to produce 4,6-diethyl-2(1H)-pyridinone (pp. 822-3).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:11]([S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH2:8][NH:16][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: O=Cc1cncc(Br)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)NCc1cncc(Br)c1Cl

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11, 5-bromo-4-chloro-pyridine-3-carbaldehyde has been reacted first with ethanesulfonamide, followed by reduction of the thus formed imine with NaBH4 in MeOH to give the title compound as a light orange solid. MS: 313.2 and 315.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.Cl>CS(C)=O.O>[F:23][C:22]1[C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1)C(=O)O
Temperature: 48 °C

Procedure:
2-(4-Hydroxyphenoxy)propanoic acid (1.80 g, 0.00988 mole) was dissolved in 15 ml of dimethyl sulfoxide. A solution of sodium hydroxide (0.8 g, 0.02 mole in 1 ml of water) was added and the reaction mixture was heated under nitrogen to 48° C. over a 27 minute period. 2-Bromo-3-fluoro-5-(trifluoromethyl)pyridine (2.40 g, 0.00984 mole) dissolved in 5 ml of dimethyl sulfoxide was added and the reaction mixture was heated at 75°-78° C. for 40 minutes. The mixture was poured into 150 ml of cold water and acidified with aqueous HCl. A gum came down. Upon work-up and purification, a fraction (0.45 g) was obtained which had an elemental analysis of, in percent by weight:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[Na+].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C(O)C.C1COCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(I)c(OC)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g (5.14 mmol) of methyl 4-iodo-3-methoxybenzoate was dissolved in 20 ml of ethanol. 10 ml of 1 N sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was dissolved in 20 ml of THF. 1.43 ml (10.3 mmol) of triethylamine and 0.54 ml (5.65 mmol) of ethyl chloroformate were added to the obtained solution, and they were stirred for one hour. The reaction mixture was filtered to obtain the precipitate. 380 mg (10.3 mmol) of sodium borohydride was added to the precipitate under cooling with ice, and they were stirred overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.CS(C)=O.[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][C:22]#[C:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:32][OH:33].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][C:22]#[C:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH:32]=[O:33]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
EDCI (127 mg, 0.66 mmol) and DMSO (62 μL, 0.87 mmol) were added sequentially to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (prepared in accordance with Example 29, step 3, 59 mg, 0.22 mmol) in benzene (2.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (47 mg, 0.24 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 2 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×2 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester that was used without further purification.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][N:6]([CH2:9][CH:10]([N:32]([CH3:46])[S:33]([C:36]3[C:37]4[CH:38]=[CH:39][N:40]=[CH:41][C:42]=4[CH:43]=[CH:44][CH:45]=3)(=[O:35])=[O:34])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][S:19]([C:22]4[C:23]5[CH:24]=[CH:25][N:26]=[CH:27][C:28]=5[CH:29]=[CH:30][CH:31]=4)(=[O:21])=[O:20])=[CH:14][CH:13]=3)[CH2:5][CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>Cl>[CH:27]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:22]([S:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH:10]([N:32]([CH3:46])[S:33]([C:36]4[C:37]5[CH:38]=[CH:39][N:40]=[CH:41][C:42]=5[CH:43]=[CH:44][CH:45]=4)(=[O:34])=[O:35])[CH2:9][N:6]4[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]4)=[CH:17][CH:16]=3)(=[O:20])=[O:21])[C:23]=2[CH:24]=[CH:25][N:26]=1
Reactant: CN(C(Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)CN1CCC2(CC1)OCCO2)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C(Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)CN1CCC(=O)CC1)S(=O)(=O)c1cccc2cnccc12
Yield: 92.3 %

Procedure:
2.57 g of the product of Example 94 was dissolved in 50 ml of 3 N hydrochloric acid, and after refluxing for 6 hours and then cooling, the reaction mixture was alkalized with saturated sodium bicarbonate aqueous solution and extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent, and resulting residue was applied to a silica gel column and eluted with chloroform/methanol (50:1) to obtain 2.22 g of the title compound in a colorless amorphous form.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl.O>O1CCOCC1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(Cl)cc12
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 53 %

Procedure:
1-Thiomorpholino-3-piperazino-5-nitro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-nitro-isoquinoline by heating for 5 hours with piperazine in dioxane at 100°C. M.p. of its hydrochloride: 245°-247°C (from water); yield: 53% of theory.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:30])[CH2:26][N:27]=[N+:28]=[N-:29])[N:17]=[CH:16]2)[C@H:6]1[F:31])(=O)C.C[O-].[Na+].C(C(O)(C([O-])=O)CC([O-])=O)C([O-])=O.C(C(O)(C([O-])=O)CC([O-])=O)C([O-])=O.O.[Na+].[Na+].[Na+].[K+].[K+].[K+]>CO>[N:27]([CH2:26][C:25]([C:18]1[N:17]=[CH:16][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[C@@H:6]2[F:31])[C:19]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:30])=[N+:28]=[N-:29]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN=[N+]=[N-])ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Yield: 76.7 %

Procedure:
Compound (39) (50 mg) obtained in item (6) above was dissolved in methanol (2 ml), to which was then added a 0.2M sodium methylate solution (0.2 ml) in methanol. The mixture obtained was allowed to undergo the reaction at room temperature for 20 minutes. The resulting reaction solution was neutralized with addition of ion-exchange resin, Amberlite CG-120 (H+ form) (100-200 mesh) and filtered, and the filtrate was concentrated. The solid residue obtained was washed with diethylether to give the titled compound (40) (31 mg) as an insoluble solid. Yield: 77%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:7][NH:8]2)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:7][NH:8]2
Reactant: [H][H]
Reactant: COC(=O)CC1CNc2cccc([N+](=O)[O-])c21
Agent: [Ni]
Solvent: CO
Product: COC(=O)CC1CNc2cccc(N)c21

Procedure:
2.0 g (8.5 mmol) methyl (4-nitro-2,3-dihydro-1H-indol-3-yl)-acetate in 70 mL MeOH were combined with 0.30 g Raney nickel and hydrogenated for 2 h in a hydrogen atmosphere. The catalyst was removed by suction filtering and the solution was concentrated by rotary evaporation. The residue was immediately reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)=[CH:4][CH:3]=1.NC1C=CC(N=NC2C=CC=C(C)C=2)=CC=1.NC1C=CC(N=NC2C=CC(C)=CC=2)=CC=1.NC1C=CC(N=NC2C=CC=CC=2OC)=CC=1.NC1C=CC(N=NC2C=CC=C(OC)C=2)=CC=1.NC1C=CC(N=NC2C=CC(OC)=CC=2)=CC=1.NC1C=CC(N=NC2C=CC=CC=2Cl)=CC=1.NC1C=CC(N=NC2C=CC=C(Cl)C=2)=CC=1.NC1C=CC(N=NC2C=CC(Cl)=CC=2)=CC=1.NC1C=CC(N=NC2C(C)=CC(C)=CC=2OC)=CC=1.C1C=C(S(O)(=O)=O)C=C(N=NC2C=CC(N)=CC=2)C=1.C1C(N)=CC=C(N=NC2C=CC(S(O)(=O)=O)=CC=2)C=1.C1C(C(O)=O)=CC=C(N=NC2C=CC(N)=CC=2)C=1.C1C(N=NC2C=CC(N)=C(S(O)(=O)=O)C=2)=CC=C(S(O)(=O)=O)C=1.NN=NC1C=CC=CC=1S(O)(=O)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N=Nc1ccc(N)cc1
Agent: COc1cc(C)cc(C)c1N=Nc1ccc(N)cc1
Agent: COc1ccc(N=Nc2ccc(N)cc2)cc1
Agent: COc1cccc(N=Nc2ccc(N)cc2)c1
Product: Nc1ccc(N=Nc2ccccc2)cc1

Procedure:
4-amino-2'-methylazobenzene; 4-amino-3'-methylazobenzene; 4-amino-4'-methylazobenzene; 4-amino-2'-methoxyazobenzene; 4-amino-3'-methoxyazobenzene; 4-amino-4'-methoxyazobenzene; 4-amino-2'-chloroazobenzene; 4-amino-3'-chloroazobenzene; 4-amino-4'-chloroazobenzene; 4-amino-2'-methoxy-4',6'-dimethylazobenzene; 4-aminoazobenzene-2'-sulfonic acid; 4-aminoazobenzene-3'-sulfonic acid; 4-aminoazobenzene-4'-sulfonic acid; 4-aminoazobenzene-2'-carboxylic acid; 4-aminoazobenzene-3'-carboxylic acid; 4-aminoazobenzene-4'-carboxylic acid; 4-aminoazobenzene-2',5'-disulfonic acid; 4-amino-5'-chloroazobenzene-2'-sulfonic acid; 4-amino-2',5'-dichloroazobenzene-4'-sulfonic acid; 4-amino-4',6'-dichloroazobenzene-2'-sulfonic acid; 4-amino-4',6'-dimethylazobenzene-2'-sulfonic acid; 4-amino-2'-methyl-6'-chloroazobenzene-4'-sulfonic acid; 4-aminoazobenzene-3,2'-disulfonic acid; 4-aminoazobenzene-3,3'-disulfonic acid; 4-aminoazobenzene-3,4'-disulfonic acid; 4-aminoazobenzene- 3,2',5'-trisulfonic acid; 4-amino-5'-chloroazobenzene-3,2'-disulfonic acid; 4-aminoazobenzene-3-sulfonic acid; 4-amino-3-methylazobenzene-2'-sulfonic acid; 4-amino-3-methylazobenzene-3'-sulfonic acid; 4-amino-3-methylazobenzene-4'-sulfonic acid; 4-amino-3-methylazobenzene-2',5'-disulfonic acid; 4-amino-2-methylazobenzene-4'-sulfonic acid; 4-amino-2-methylazobenzene-3'-sulfonic acid; 4-amino-2-methylazobenzene-2',5'-disulfonic acid; 4-amino-3-methoxyazobenzene-3'-sulfonic acid; 4-amino-3-methoxyazobenzene-4'-sulfonic acid and 4-amino-3-methoxyazobenzene-2',5'-disulfonic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.CO>>[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][N:22]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[CH2:18][O:17]1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC1(C)OCC(CN)O1
Solvent: CO
Product: CC1(C)OCC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)O1

Procedure:
5-Nitro-isochromen-1-one (8 g, 0.04 mol) and (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (5 g, 0.04 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (330 g of silica gel, 0-50% EtOAc/Hexane) to give a bright yellow solids.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]3)O1.Br[C:23]1[CH:24]=[C:25]([CH:29]([CH:36]2[CH2:38][CH2:37]2)[NH:30][S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH:26]=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(Cl)Cl>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].CN(C=O)C>[C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:23]1[CH:24]=[C:25]([CH:29]([CH:36]3[CH2:38][CH2:37]3)[NH:30][S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH:26]=[N:27][CH:28]=1)[CH:18]=[CH:17]2)#[N:20]
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2ccc3cc(C#N)ccc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc3cc(C#N)ccc3c2)c1)C1CC1
Yield: 27.1 %

Procedure:
A mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthonitrile (335 mg, 1.200 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (319 mg, 1 mmol), sodium carbonate (2 M) in water (1.000 mL, 2.000 mmol), PdCl2(dppf).CH2Cl2 adduct (40.8 mg, 0.050 mmol) in DMF (4.000 mL) was heated to 100° C. for 30 min. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (10-100% EtOAc/heptane; SNAP25 column) giving the title compound (106 mg, 27%) as a white solid 1H NMR (400 MHz, MeOD) δ ppm 0.43-0.55 (m, 1H) 0.56-0.69 (m, 2H) 0.69-0.83 (m, 1H) 1.28 (t, J=7.36 Hz, 3H) 1.25-1.39 (m, 1H) 2.82-3.10 (m, 2H) 3.95 (d, J=9.09 Hz, 1H) 7.73 (dd, J=8.53, 1.45 Hz, 1H) 8.00 (dd, J=8.59, 1.71 Hz, 1H) 8.15 (s, 1H) 8.17 (s, 1H) 8.28-8.35 (m, 2H) 8.44 (s, 1H) 8.65 (d, J=2.02 Hz, 1H) 8.90 (d, J=2.08 Hz, 1H). LC-MS (M+1) 392.2. Enantiomers were separated by chiral HPLC (IA 21×250 mm, flow rate: 14 mL/min, 60% heptane 20% methanol 20% ethanol) and yielded enantiomer −1 with retention time (14.10 min) and enantiomer-2 with retention time (18.16 min).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)/[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1ccc(N)c(C(C)C)c1)NC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)c(C(C)C)c1)NC(C)=O

Procedure:
methyl (2Z)-2-(acetylamino)-3-(4-amino-3-isopropylphenyl)acrylate (752 mg, 2.72 mmole) and 10% Pd/C (143 mg) stirred in ethanol (20 mL) under 1 atmosphere of hydrogen for 16 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the titled compound.
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:18])[CH2:3]1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:18])[CH2:3]1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)C(F)C1
Agent: I
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C(F)C1
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of compound 136 (0.07 g, 0.283 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.16 g, 0.566 mmol) at room temperature and stirred for overnight (16 h). Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 137 (0.09 g, 90%) as a solid. mp 115-117° C.; 1H NMR (DMSO-d6) δ 1.79-2.09 (m, 4H), 2.26 (s, 3H), 2.74-2.90 (m, 2H), 3.13-3.17 (m, 1H), 4.68 (dddd, 1H, J=4.8, 9.6, 9.6, 48.5
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]\OCC)[C:5]([F:13])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:29][C:28]1[C:23]2[N:24]([C:8]([C:6]3[C:5]([F:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:9][N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ncccc1Cl
Reactant: CCO/C=C\c1nc(Cl)ncc1F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cnc(Cl)nc1-c1cnc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
25.2 g of the compound [67-1] was dissolved in a mixed solvent of 320 mL of 1,4-dioxane and 32 mL of water. Then, 22.2 g of N-bromosuccinic acid imide was added under an ice-cold condition, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, 16.0 g of 2-amino-3-chloropyridine was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The obtained organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, hexane was added, and the mixture was stirred for 30 minutes. The solid was taken by filtration, and dried under reduced pressure to obtain 20.0 g of 8-chloro-3-(2-chloro-5-fluoropyrimidin-4-yl)imidazo[1,2-a]pyridine [67-2] (hereinafter, referred to as the compound [67-2]) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCc2ccccc2)cc1

Procedure:
A mixture of 7 g. of ethyl p-[(5-phenylpentyl)amino]benzoate (prepared as described in Example 46), 7 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3 hours. The mixture is acidified with concentrated hydrochloric acid while hot, diluted with water, cooled and filtered. The solid is washed with water to give white crystals, m.p. 141°-143° C. Recrystallization from ethanol gives white crystals, m.p. 142°-144° C.