Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.[CH3:26]OC(OC)OC.O>C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:26]=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: COC(OC)OC
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nnco2)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzohydrazide (preparation 53, 0.16 g, 0.24 mmol) and trimethylorthoformate (0.24 mL, 1.44 mmol) in acetic acid (3 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (1:1 hexanes/ethyl acetate) gave the title compound (0.05 g, 60%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([CH2:12][NH:13][C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19]([NH2:21])=[O:20])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].ClCCl.C(OC(N=[C:31]=[S:32])=O)C.FC(F)(F)C(O)=O>C(O)C>[CH2:1]([O:5][C:6]1[C:7]([CH2:12][N:13]2[C:14]3[N:15]=[CH:16][NH:17][C:18]=3[C:19](=[O:20])[NH:21][C:31]2=[S:32])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)N=C=S
Reactant: CCCCOc1cccnc1CNc1nc[nH]c1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CCCCOc1cccnc1Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To 4-{[(3-butoxypyridin-2-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.991 g, 3.43 mmol, obtained from Example 19(b)) was added dichloromethane (20 mL), ethoxycarbonyl isothiocyanate (0.47 mL, 4.11 mmol) and absolute ethanol (2 mL). After stirring o.n., more ethoxycarbonyl isothiocyanate (0.23 mL) was added and the solution was heated to reflux for 2 h upon, which more ethoxycarbonyl isothiocyanate (0.10 mL) was added and the solution was refluxed for 2 h more. The volatiles were removed in vacuo and 1 N sodium hydroxide (20 mL) was added and the suspension was heated to reflux for 4 h. After cooling to r.t. the solution was neutralized with 2 N hydrochloric acid. The resulting precipitate was filtered, washed with water and dried resulting in 0.699 g of crude product. Purification was achieved with a portion of the crude material (300 mg) by trituration with methanol and dichloromethane and then concentrating the organic layer followed by prep HPLC providing 0.103 g (16% yield, 0.231 mmol) of the title compound as its trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=CC(OC[CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCN(C)C)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H) 8.14 (m, 1H) 8.10 (m, 1H) 8.00 (m, 1H) 7.89 (t, J=8.0 Hz, 1H) 7.69 (s, 1H) 7.28 (d, J=8.08 Hz, 1H) 7.20 (d, J=8.08 Hz, 1H) 4.68 (t, J=5.0 Hz, 2H) 3.80 (t, J=5.0 Hz, 2H) 3.43 (q, J=7.32 Hz, 2H) 3.13 (s, 6H) 1.33 (t, J=7.32 Hz, 3H). [M+H] calc'd for C23H25ClN3O3S, 458; found, 458.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33]OS(C3C=CC(C)=CC=3)(=O)=O)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.O>C(#N)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33][SH:10]3[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]3)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(-c2[nH]cc(CCC[SH]3CCNCC3)c2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
163 mg (1.18 mmol) of potassium carbonate and 122 μl (1.29 mmol) of thiomorpholine were added to a solution of 450 mg (1.07 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 23(iv) above] in 50 ml of acetonitrile. The resulting mixture was heated under reflux overnight. After cooling the reaction mixture to room temperature, water was added and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 95:5 by volume mixture of ethyl acetate and methanol as the eluant to give 340 mg (yield 83%) of the title compound as a pale yellow powder.
Reaction SMILES: C1C=CC=CC=1.C1(C)C=CC=CC=1.[C:14]1([CH:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:21]2[CH2:26][C:25](=O)[N:24]([N:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[C:23](=O)[CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B#B>O1CCCC1.B(F)(F)F.C(OCC)C>[C:38]1([CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]2[CH2:22][CH2:23][N:24]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[CH2:25][CH2:26]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1cccc(C=NN2C(=O)CN(C(c3ccccc3)c3ccccc3)CC2=O)n1
Agent: B#B
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(CNN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
By way of illustration, the first step of Scheme A is shown. Iminodiacetic acid, disodium salt monohydrate is reacted with thionyl chloride to give diethyliminodiacetate. This reaction is conducted in ethanol. Time and temperature are not deemed critical to the conduct of this reaction. Time varies from 20 hrs. to 72 hrs. depending on the particular temperature employed. The resulting product from the first step -- diethyliminodiacetate -- is then treated with chlorodiphenylmethane. Time and temperature are typically in the range of 24 hrs. to 72 hrs. and 70°-150° C. This reaction is typically carried out at a temperature of 70°-80° C for 72 hrs. to afford diethyl-N-benzhydryliminodiacetate. Treatment of diethyl-N-benzhydryliminoacetate with hydrazine hydrate affords 5-diphenylmethyl-3,7-diketo-1,2-dihydro-1,2,5-triazepine. This reaction is conveniently carried out in the presence of methanol. Typically this reaction is carried out at reflux and a reaction time of 20 hrs. Treatment of 5-diphenylmethyl-3,7-diketo-1,2-dihydro-1,2,5-triazepine with 6-methylpyridine-2-carboxaldehyde affords 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine. This reaction is carried out in the presence of a solvent, a preferred solvent being benzene or toluene. Time and temperature are not critical, with reflux temperature and reaction time of 4 hours being typical. Reduction of the ketone groups on the piperazine ring is effected by the treatment of 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine with a mixture of diborane in tetrahydrofuran and boron trifluoride in diethyl ether. This procedure affords 1-diphenylmethyl-4-(6-methyl-2-pyridylmethylamino)piperazine. 1-Diphenylmethyl-4-(6-methyl-2-pyridylmethylamino)piperazine is then treated with 0.1M iodine/MeOH to afford the dehydrogenated product -- 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)piperazine. Dehydrogenation of 1-diphenylmethyl-4-(6-methyl-2-pyridylmethylamino)piperazine can also be accomplished using palladium-on-carbon in the presence of methanol in place of 0.1M iodine/MeOH reagent.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([N:16]([OH:37])[CH:17]([C:19]1[C:20]([Cl:36])=[C:21]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][NH2:31])=[O:29])[CH:22]=[CH:23][CH:24]=1)[CH3:18])(=[O:15])[CH3:14].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[O:7]=[C:6]1[O:29][C:28]([C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[NH:25][C:21]2[C:20]([Cl:36])=[C:19]([CH:17]([N:16]([OH:37])[C:13](=[O:15])[CH3:14])[CH3:18])[CH:24]=[CH:23][CH:22]=2)=[N:30][NH:31]1
Reactant: CC(=O)N(O)C(C)c1cccc(Nc2ccccc2C(=O)NN)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(O)C(C)c1cccc(Nc2ccccc2-c2n[nH]c(=O)o2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
CDI (0.63 g, 3.9 mmoles) is added to a solution of 2-[[3-[1-(acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid hydrazide (1.4 g, 3.9 mmoles) and triethylamine (0.81 g, 8.1 mmoles,) in 25 mL of THF at 0° C. under an argon atmosphere. The reaction mixture is stirred at 0° C. for 30 minutes under Ar, and then at room temperature overnight. The reaction mixture is partitioned between 50 mL of 1.0 N HCl and 50 mL of EtOAc. The organic layer is washed with 100 mL of 1.0 N HCl, 100 mL of water, and 100 mL of brine. Drying over MgSO4 and evaporation of the solvent gives an off white solid. Flash chromatography over silica gel in EtOAc gives 0.27 g (18%) of N-[1-[3-[[2-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl) phenyl]amino]-2-chlorophenyl]ethyl] -N-hydroxyacetamide; m.p. 186°-189° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=2)=[CH:4][CH:3]=1.N#N.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH:52]=[N:51][CH:50]=[N:49]1>S(Cl)(Cl)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)([N:48]2[CH:52]=[N:51][CH:50]=[N:49]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: c1nc[nH]n1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1cncc1C(c1ccc(Cl)cc1)(c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C)n1cncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
6[(4chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one (330 mg, 0.633 mMol) was dissolved in 4 mL of thionyl chloride and stirred at ambient temperature under a stream of dry N2 for 2 hours. The reaction mixture was then concentrated under vacuum and toluene (5 mL) was added to the reaction mixture which was subsequently concentrated under vacuum to give a yellow solid. 210 mg of the yellow solid was dissolved in 5.0 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added 800 mg of potassium carbonate and 300 mg of 1,2,4-triazole and the reaction mixture was subsequently heated to 80° C. and stirred overnight at this temperature. The reaction mixture was then concentrated under vacuum and partitioned between EtOAc and water. The EtOAc layer was washed 3 more times with water and then with brine. The EtOAc layer was then dried over Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The solid was chromatographed on flash silica gel eluting with a gradient of MeOH/DCM/NH4OH (2/9810.1) to MeOH/DCM/NH4OH (7/93/0.1) to give 150 mg of the titled product as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>CC#N.[Bi](Br)(Br)Br>[CH2:19]([CH:11]1[CH2:10][CH:9]([O:8][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH2:13][CH:12]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCOC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CC1CC
Reactant: O=C1CCOCC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CC(OC2CCOCC2)CC1CC
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 140.5 %

Procedure:
To a solution of ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.200 g, 0.666 mmol, Example #22 Step D) in MeCN (4.5 mL) was added triethylsilane (0.160 mL, 1.00 mmol) and bismuth(III) bromide (0.020 g, 0.045 mmol). The reaction mixture was stirred at ambient temperature for about 1 min followed by dropwise addition of dihydro-2H-pyran-4(3H)-one (0.100 g, 0.998 mmol). The reaction mixture was stirred at ambient temperature for about 15 min. The reaction was filtered through an Acrodisc® and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography using a gradient of 10-100% EtOAc in heptane to give ethyl 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate (0.253 g, 94%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J=7.1, 2H), 4.05-3.98 (m, 1H), 3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H), 3.46-3.36 (m, 2H), 2.80 (q, J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H), 2.09-1.93 (m, 3H), 1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd, J=11.1, 7.4, 5.2, 1H), 1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57]([CH3:62])[CH:58]=[N:59]2)=[CH:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:52]5[CH:61]=[C:60]6[C:55]([CH:56]=[C:57]([CH3:62])[CH:58]=[N:59]6)=[CH:54][CH:53]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: Cc1cnc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cnc2cc(-c3ccc(C(C(N)=O)N4CCC5(CC4)CN(C4CC4)C(=O)CO5)c(F)c3)ccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.223 mmol) in dry 1,4-dioxane (1.5 mL) was treated with bis(pinacolato)diboron (0.268 mmol), potassium acetate (0.499 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.011 mmol). The solution was degassed with nitrogen, sealed, and stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and was treated with 7-bromo-3-methylquinoline (0.223 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.011 mmol) and 2M aq potassium carbonate (0.669 mmol). The reaction vessel was purged with nitrogen gas, sealed, and irradiated in a Biotage Initiator Microwave at 120° C. for 15 minutes. The resulting black mixture was diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was treated with Silicycle Si-thiol (30 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-10% methanol/dichloromethane followed by 30% methanol/dichloromethane) and resolution by chiral HPLC (Chromegachiral CC4, methanol) afforded the title compound in >99% ee (31% yield). MS(ES)+ m/e 503.2 [M+H]+. αD=+ 38 deg (c=0.03, methanol).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[C:52](=[O:65])[C:53]([C:62](O)=[O:63])=[CH:54][N:55]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH:56]=2)=[CH:47][CH:46]=1.[NH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[C:74]([NH2:85])=[N:75][CH:76]=[C:77]([C:79]3[CH:80]=[N:81][N:82]([CH3:84])[CH:83]=3)[CH:78]=2)=[CH:69][CH:68]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:85][C:74]1[C:73]([C:70]2[CH:69]=[CH:68][C:67]([NH:66][C:62]([C:53]3[C:52](=[O:65])[C:51]([C:48]4[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=4)=[CH:56][N:55]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH:54]=3)=[O:63])=[CH:72][CH:71]=2)=[CH:78][C:77]([C:79]2[CH:80]=[N:81][N:82]([CH3:84])[CH:83]=2)=[CH:76][N:75]=1
Reactant: O=C(O)c1cn(CC(F)(F)F)cc(-c2ccc(F)cc2)c1=O
Reactant: Cn1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CC(F)(F)F)cc(-c5ccc(F)cc5)c4=O)cc3)c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
HOBt (51 mg), HATU (215 mg), DMAP (23 mg) and DIPEA (131 μl) were added to a solution of the Compound obtained in Step 2 of Example 9 (131 mg) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The compound obtained in Step 1 of Example 47 (100 mg) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 50° C. for 1.5 hours and returned to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified by PLC [dichloromethane:methanol=15:1 (v/v)] to give 64 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([CH:19]([NH2:28])[CH3:20])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
A mixture of 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (50 mg, 0.2 mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65° C., in a sealed tube, for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (22 mg, 0.35 mmol) was added. The reaction was heated at 65° C. for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step. LCMS calculated for C15H15ClFN2O2 (M+H)+: m/z=309.1. found: 309.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:26])=[O:25])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Brc1cncc(-c2cnc3c(c2)CCCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
6-(5-Bromo-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (190 mg, 0.67 mmol) and benzoyl isocyanate (220 mg, 1.3 mmol) are mixed in 3.0 mL of DCM and the mixture is stirred at 50° C. for 2 hrs and room temperature for 16 hrs. Then the solvent is removed and the residue is suspended in 3.0 mL of EtOH. K2CO3 (160 mg, 1.1 mmol) is added and the mixture is heated at 70° C. for 30 min. Then the solvent is removed and the residue is partitioned between water (20 mL) and EtOAc (50 mL). The aqueous layer is separated and extracted with DCM (2×50 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (10 mL) and the solid formed is filtered, washed again with EtOAc (2×10 mL) and dried to give 158 mg of 6-(5-bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S+:26]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][C:20]=1[CH3:47].C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:62]([O:64][CH2:65][CH2:66]Cl)=[CH2:63]>CS(C)=O>[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH:62]([O:64][CH2:65][CH2:66][O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S+:26]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:31][CH:32]=2)[C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)=[CH:21][C:20]=1[CH3:47])=[CH2:63]
Reactant: Cc1cc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc(C)c1O
Reactant: C=COCCCl
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CS(C)=O
Product: C=COCCOc1c(C)cc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 80 °C
Reaction time: 19 h

Procedure:
4-Hydroxy-3,5-dimethylphenyldi(4-t-butylphenyl)sulfonium perfluorobutanesulfonate salt (28.6 g), potassium carbonate (8.10 g), and N,N,N′,N′-tetramethylethylenediamine (0.46 g) were dissolved in dimethyl sulfoxide (142 g). Chloroethyl vinyl ether (6.08 g) was added to the solution, followed by heating to 80° C. The reaction mixture was stirred for 19 hours and cooled to 30° C. or lower. After removal of solid through filtration, water (20.9 g) was added to the filtrate, and the aqueous layer was washed three times with hexane (85.1 g). To the washed aqueous layer, dichloromethane (226 g) and water (141 g) were added under stirring, whereby the target substance was extracted to the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer was shifted to 7. The solvent was removed by means of a rotary evaporator, to thereby yield 27.4 g of a brown oily substance. Through 1H-NMR and ion chromatography, the substance was identified to be 4-vinyloxyethoxy-3,5-dimethylphenyldi(4-t-butylphenyl)sulfonium perfluorobutanesulfonate salt.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:17][CH3:18])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.Cl>[OH-].[Na+]>[CH3:18][S:17][C:7]1[NH:8][C:9]2[C:14]([C:15](=[O:16])[C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCOC(=O)c1c(SC)nc2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1[nH]c2ccccc2c(=O)c1C(=O)O
Yield: 85 %

Procedure:
4-Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g, 30 mmol) was heated under reflux in NaOH solution (10%, 100 mL) for 1.5 h. After cooling, the mixture was acidified with concentrated HCl to pH 4. The resulting solid was collected via filtration, washed with water (100 mL) and MeOH (100 mL) to give 2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-16) as a white solid (6 g, 85%). 1H NMR (CDCl3) δ 16.4 (br s, 1 H), 11.1 (br s, 1 H), 8.19 (d,J=8 Hz, 1H), 8.05 (d,J=8 Hz, 1H), 7.84 (t,J=8, 8 Hz, 1H), 7.52 (t,J=8 Hz, 1H), 2.74 (s, 3H); ESI-MS 235.9 m/z (MH+).