Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:30]4[CH:31]=[C:26]([F:25])[CH:27]=[CH:28][C:29]=4[F:32])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(F)ccc1F
Yield: 76.8 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,5-difluorophenylboronic acid (available from Combi-Blocks Inc.; 63 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,5′-difluoro-biphenyl-2-carboxylic acid (71 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.48-8.52 (m, 2H), 8.34 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.75-7.79 (m, 1H), 7.59 (d, J=6.8 Hz, 1H), 7.27-7.37 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:12]=2[N:13]=[C:14](S(C)(=O)=O)[N:15]=1.[NH2:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[C:34]([NH:41][CH2:42][CH2:43][NH2:44])[N:33]=1>>[NH2:31][C:32]1[N:33]=[C:34]([NH:41][CH2:42][CH2:43][NH:44][C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:11]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:12]=3[N:13]=2)[CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(Nc3ccc(Cl)cc3Cl)c2C1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Nc3ccc(Cl)cc3Cl)c2C1

Procedure:
Following Example 7, treatment of tert-butyl 4-[(2,4-dichlorophenyl)amino]-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate with 2-amino-3-nitro-6-(2-aminoethylamino)pyridine gave tert-butyl 2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-[(2,4-dichlorophenyl)amino]-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([O:23]CC)=[O:22])(=[O:10])=[O:9])=[C:4]([CH3:26])[CH:3]=1.FC1C=CC(S(N(S(C2C=CC(F)=CC=2C)(=O)=O)C2SC3CCCCC=3C=2C(OCC)=O)(=O)=O)=C(C)C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([OH:23])=[O:22])(=[O:10])=[O:9])=[C:4]([CH3:26])[CH:3]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C)sc2c1CCCC2
Agent: CCOC(=O)c1c(N(S(=O)(=O)c2ccc(F)cc2C)S(=O)(=O)c2ccc(F)cc2C)sc2c1CCCC2
Product: Cc1cc(F)ccc1S(=O)(=O)Nc1sc2c(c1C(=O)O)CCCC2

Procedure:
Prepared by proceeding in a similar manner to Example 2, starting from a 2:1 mixture of ethyl 2-(4-fluoro-2-methylbenzenesulphonylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate and ethyl 2-[bis-(4-fluoro-2-methyl-benzenesulphonyl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Intermediate 32)
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:19])OC(C)(C)C)[C:8](=[O:20])[NH:7][C:6]2[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:5]1=2)(=[O:3])[CH3:2].[C:27]([N:34]([CH3:40])[C@H:35](C(O)=O)[CH3:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1.CCOCC.CCOC(C)=O>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:19])[C@@H:35]([N:34]([CH3:40])[C:27](=[O:28])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH3:36])[C:8](=[O:20])[NH:7][C:6]2[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C#N)ccc2NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2cc(C#N)ccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A rt solution of tert-butyl(2S,3S)-1-acetyl-8-cyano-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (144 mg, 402 μmol) in 4 M HCl in dioxane (2.01 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in DMF (1.34 ml), and Boc-N-methyl-L-alanine (89.9 mg, 442 μmol), N,N-diisopropylethylamine (278 μl, 1.61 mmol), and HBTU (168 mg, 442 μmol) were added at 0° C. The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-1-acetyl-8-cyano-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (123 mg, 69%) as a white solid. MS m/z 466 (MNa)+.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C@@H:5]2[N:9]1C(=O)C2C(=CC=CC=2)C1=O.NN.[ClH:23]>C(O)C>[ClH:23].[F:1][C:2]1([F:20])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][C@@H:5]2[NH2:9]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Agent: Cl
Agent: NN
Solvent: CCO
Product: N[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-((1R,2S,4R)-5,5-difluorobicyclo[2.2.1]-heptan-2-yl)isoindoline-1,3-dione (0.58 g, 2.09 mmol) in ethanol (anhydrous, 30 mL) was added hydrazine (0.10 mL, 3.14 mmol). After refluxing this mixture under nitrogen for 5 h, it was cooled in an ice bath, and hydrochloric acid (37%, 0.50 mL) was added. After stirring at 60° C. for 1.5 h, the mixture was cooled to ambient temperature. After the white solid was removed by filtration, the filter cake was washed with methanol, and the filtrate was conc. in vacuo. The resulting residue was diluted in ˜50 mL of water, filtered, and the filtrate was washed with diethyl ether (30 mL×3). The filtrate was then treated with sodium carbonate monohydrate to saturation, and the aqueous layer was extracted with diethyl ether (50 mL×3). These organic layers were combined, dried over potassium carbonate (solid), and filtered. The solution was treated with hydrochloric acid (1M aqueous, 4 mL), stirred for 5 min, and then concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH2:22][CH3:23])[C:18]([N+:19]([O-])=O)=[C:14]2[CH:13]=[CH:12][CH:11]=1.O.C(O)(=O)C>C(O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH2:22][CH3:23])[C:18]([NH2:19])=[C:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1N
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (5 mg) was suspended in ethanol (2 mL), and then water (1 mL), acetic acid (0.5 mL) and zinc powder (10 mg) were added and the mixture was heated and stirred at 80° C. for 30 minutes. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain [7-(2-chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine as crude crystals. These were dissolved in tetrahydrofuran (1 mL) without further purification, and after adding propionaldehyde (0.015 mL) and 3 M aqueous sulfuric acid (0.071 mL), sodium borohydride (5.4 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure and the residue was purified by preparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain the title compound (6 mg) as a light yellow oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:17]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([NH:6][C:7]3[O:11][N:10]=[C:9]([CH3:12])[C:8]=3[CH3:13])=[O:14])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3ccc(-c4ccccc4)cc3)CC2)c1C
Yield: 57 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (265 mg, 0.923 mmol), 1-biphenyl-4-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (180 mg, 57.1%) as solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1>COCCO>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 11 %

Procedure:
7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (166 mg, 0.87 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (259 mg, 0.87 mmol) were suspended in 2-methoxyethanol (9 ml), and heated to 120° C. for 18 hours. Concentration afforded a brown residue. Purification by preparative TLC (5% MeOH/CH2Cl2) gave a slightly impure yellow oil which was then triturated with acetone to give the title compound as a white solid, 45 mg. (11% yield) 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.52 (s, 1H), 8.64-8.81 (m, 2H), 8.22 (s, 1H), 7.69-7.75 (m, 1H), 7.42-7.59 (m, 3H), 7.12-7.26 (m, 2H), 3.19 (s, 3H), 2.74-2.80 (m, 2H), 2.49-2.60 (m, 2H), 1.95-2.20 (m, 5H); MS (m/e) 451 (M+1); mp 244-246° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[C:2]#[CH:3].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc(N)cc1

Procedure:
4-(Prop-2-ynyloxy)nitrobenzene (0.910 g, 5.13 mmol), iron (1.42 g, 25.3 mmol), and NH4Cl (0.719 g, 12.8 mmol) were vigorously stirred in EtOH/water (1:1, 55 mL) at 70° C. for 15 minutes. The reaction mixture was filtered hot through Celite and concentrated in vacuo. The residue was suspended in 10% 2N ammoniacal methanol in dichloromethane, sonicated, and filtered through Celite. Concentration gave 4-(prop-2-ynyloxy)aniline as a brown oil which was used without further purification. In general, isolated prop-2-ynyloxyanilines were unstable and were therefore used immediately after the second filtration. 1H NMR (CDCl3): δ 6.82 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 4.61 (d, J=2.4 Hz, 2H), 2.50 (t, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH3:24]>CN(C=O)C>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a mixture of 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 15 ml of DMF was added 27 mg of lithium hydride in a stream of argon, and it was stirred for 30 minutes at room temperature. To the mixture was then added 568 mg of n-propyl iodide. The mixture was then stirred for 2 hours. After the termination of the reaction, the mixture was concentrated under reduced pressure. To the resulting residue was added water and ethyl acetate, and extracted. The resulting organic phase was separated, washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 584 mg of 2,3-dihydro-2-[(4-methylphenyl)imino)-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and hexane) as a low polarity substance and 179 mg of 2-[N-(4-methylphenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=4)=[CH:14][N:13]3[CH:27]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:21]=[CH:22][CH:23]=4)=[CH:14][N:13]3[CH:27]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
164 mg of sodium borohydride are added portionwise to 150 mg of 1-{3-[2-(4-chloro-phenyl)imidazo[1,2-a]pyridin-6-yl]phenyl}ethanone (compound obtained in 8.1) dissolved in 20 ml of methanol. The mixture is then stirred at ambient temperature for one hour and the solvent is then evaporated off under reduced pressure. The residue is taken up in between water and dichloromethane, the organic phase is separated by settling out and dried over sodium sulphate and the solvent is then evaporated off under reduced pressure. The residue is triturated in diisopropyl ether and recovered by filtration and then dried in a dessicator under reduced pressure. 124 mg of compound are obtained. Mp=174-176° C. 1H NMR (DMSO-d6, δ in ppm): 1.37 (d, J=6.5 Hz, 3H); 4.79 (m, 1H); 5.19 (d, J=4.2 Hz, 1H); from 7.31 to 7.69 (m, 8H); 7.97 (m, J=8.6 Hz, 2H); 8.41 (s, 1H); 8.84 (m, 1H). M+H=349.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:21]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:21]=12)=[O:18]
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(O)c2)c1
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2nccc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)c2s1
Temperature: 68 °C

Procedure:
A mixture of N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide (270 mg, 1.1 mmol), methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (300 mg, 1.3 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in 10 ml of anhydrous DMSO was heated at 68° C. for 16 hours, cooled to room temperature and partitioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with more EtOAc (2×50 ml). All the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, and evaporated to dryness to give the crude, which was purified by silica gel chromatography eluted with 1˜2% of MeOH in CHCl3 to give methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate as light brown oil. Yield: 170 mg, 37%.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1cc(NN)nc2ncccc12
Solvent: ClCCl
Product: Cc1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydrazinyl-4-methyl-1,8-naphthyridine prepared above (84 mg, 0.482 mmol) in CH2Cl2 was added 3,5-dichlorophenyl isocyanate (91 mg, 1.0 eq). The resulting mixture was stirred at room temperature overnight. The resulting precipitate was filtered off and washed with EtOAc to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3 H) 6.78 (s, 1 H) 7.05 (t, J=1.90 Hz, 1 H) 7.23 (dd, J=7.91, 4.40 Hz, 1 H) 7.61 (br. s., 2 H) 8.22 (dd, J=8.06, 1.90 Hz, 1 H) 8.57 (br. s., 1 H) 8.68 (dd, J=4.40, 1.76 Hz, 1 H) 8.98 (s, 1 H) 9.22 (br. s., 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O.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].O1CCOCC1>[F:20][C:21]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([N:9]3[C:17]4[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=4[N:11]=[CH:10]3)[CH:5]=[CH:6][C:7]=2[F:8])[C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cc(F)ccc3C#N)c2)c1=O
Temperature: 70 °C
Yield: 58.4 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one (0.64 g, 2.0 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.99 g, 4.0 mmol) and potassium phosphate (0.68 g, 3.2 mmol) were placed in a flask with 1,4-dioxane (3 ml), and water (2 drops) was added. The mixture was degassed with nitrogen for 15 min before adding tris(dibenzylideneacetone)-dipalladium(0) (90 mg, 0.10 mmol) and tri-tert-butylphosphine (10% wt in hexanes, 0.20 ml, 0.10 mmol). The resulting mixture was heated at 70° C. for 16 h. The reaction mixture was allowed to cool, and then partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel, eluting with dichloromethane on a gradient of ethanol (1-4%), gave a white solid. This solid was triturated with ethanol and filtered, yielding pure 5,2′-difluoro-5′-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile as a white solid (423 mg, 60%): δH (400 MHz, d6-DMSO) 3.54 (3H, s), 6.69 (1H, d, J 7), 7.59-7.62 (2H, m), 7.71 (1H, t, J 9), 7.79 (1H, dd, J 9 and 7.84-7.90 (2H, m), 8.16 (1H, dd, J 9 and 6), 8.39 (1H, s); m/z (ES+) 363 [MH+].
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:35]5[CH:34]=[N:33][N:32]([CH:29]6[CH2:30][CH2:31][O:27][CH2:28]6)[CH:36]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(C4CCOC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (4.7 mg). LCMS (M+H)+: m/z=475.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.Cl.[NH2:24][OH:25]>N1C=CC=CC=1.C(Cl)Cl>[NH2:9][CH2:10][C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:8](=[N:24][OH:25])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:22]
Reactant: O=C1CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCC(=O)Nc1ccc([N+](=O)[O-])cc1C(=NO)c1ccccc1F

Procedure:
A solution of 50 g (0.167 mol) of 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one and 17.4 g (0.25 mol) of hydroxylamine hydrochloride in 200 ml of pyridine is heated to reflux overnight under argon. The mixture is concentrated in a rotary evaporator and the residue is taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. The aqueous phase is extracted with chloroform overnight in a perforator. After drying and removing the solvent, the residue is combined with the crude product obtained above, suspended in 200 ml of methylene chloride and filtered off. There is obtained 2-amino-2'-[o-fluoro-α-(hydroxylimino)benzyl]-4'-nitro-acetanilide of melting point 198°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11]Cl)=[N:9][CH:10]=1)=[O:5].[CH3:14][NH:15][CH3:16]>>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11][N:15]([CH3:16])[CH3:14])=[N:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1cnc(CCl)n1C
Reactant: CNC
Agent: Cl
Product: COC(=O)c1cnc(CN(C)C)n1C

Procedure:
Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and dimethylamine (33% solution in ethanol), the title compound was obtained as brown viscous oil (85% yield). MS: m/e=198(M+H+).