Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:37])([F:36])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)=[N:19]2)=[CH:14][CH:13]=1>CS(C)=O>[F:37][C:10]([F:9])([F:36])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:4][CH:30]4[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To an oven-dried round bottomed flask was added sodium hydride (60% oil immersion, 0.380 g, 9.50 mmol) and anhydrous dimethyl sulfoxide (30 mL). Gas evolution occurred, and the solution was stirred at room temperature for 15 minutes. Trimethylsulfoxonium iodide (2.10 g, 9.54 mmol) was added, the flask neck was rinsed with anhydrous dimethyl sulfoxide (5 mL), and the reaction was stirred for 15 minutes. To the reaction was added (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C17) (3.22 g, 7.98 mmol) as a solid. The reaction was stirred at room temperature for 30 minutes, and then quenched with water and extracted with 1:1 ethyl acetate/hexanes (2×). The combined organic layers were washed with water (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as a yellow oil (1.50 g, 41%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.39 (dd, J=6.6, 5.9 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 4.19 (dt, J=14.0, 7.0 Hz, 2H), 2.64-2.52 (m, 2H), 1.97 (ddd, J=8.5, 5.3, 4.2 Hz, 1H), 1.71-1.61 (m, 1H), 1.42-1.32 (m, 1H), 1.29 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 418 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2ccc3ccccc3c2)ncn1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc2cc(-c3cc(-c4ccc5ccccc5c4)ncn3)ccc2c1
Yield: 19 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 3.9 g of 4-chloro-6-(naphthalen-2-yl)pyrimidine obtained in Step 1, 2.8 g of 2-naphthaleneboronic acid, 1.7 g of sodium carbonate, 0.14 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 1.4 g of 2-naphthaleneboronic acid, 0.9 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1, so that a pyrimidine derivative Hd2npm, which was the objective substance, was obtained (yellow white powder, yield of 19%). A synthesis scheme (h-2) of Step 2 is shown below.
Reaction SMILES: Br.[O:2]1[C:8]2[C:9]([OH:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>ClCCl>[OH:13][C:9]1[C:8]2[O:2][CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc2c1OCCNC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-1,4-benzoxazepin-9-ol. hydrobromide (Preparation 85) (55.7 g, 226 mmol) in dichloromethane (DCM) (550 ml) was treated with triethylamine (47.3 ml, 339 mmol) and stirred for 20 minutes. This mixture was cooled in ice/water to ca 5° C. and treated slowly with a solution of BOC2O (59.6 ml, 249 mmol) in dichloromethane (DCM) (200 ml) at such a rate as to keep the internal temperature below 10° C. When the addition was complete, the mixture was allowed to warm to room temperature, stirred for 2 hours and allowed to stand at room temperature overnight. The mixture was washed with 0.5M hydrochloric acid (2×250 ml) and water (250 ml), dried (sodium sulphate) and evaporated to give the title compound as a pale brown solid (60.5 g)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[Se:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+].O>C(O)(=O)C.O1CCCC1.CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[Se:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[se]c(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1[se]c(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 89.5 %

Procedure:
The ethyl 4-(4-chlorobenzyl)-2-(morpholin-4-yl)-1,3-selenazole-5-carboxylate (35.0 mg, 0.0846 mmol) was placed in a round bottomed flask equipped with a stirbar. Tetrahydrofuran (1.00 mL) and methanol (0.1 mL) were added and the mixture was stirred to give a light yellow solution. A solution of lithium hydroxide in water (2.0 M, 0.423 mL, 0.846 mmol) was added in a single portion, and the resulting mixture was stirred under an atmosphere of nitrogen at room temperature overnight. LCMS analysis of the reaction indicated that starting material still remained; only a small amount of it had been hydrolyzed to the product. Additional tetrahydrofuran (2 mL) and lithium hydroxide in water (2.0 M, 0.423 mL, 0.846 mmol) were added and the reaction was heated overnight at 50° C. under an atmosphere of nitrogen. LCMS analysis indicated that the reaction was 90% complete. The reaction was heated at 60° C. for a further 8 hours. LCMS analysis indicated complete hydrolysis. The reaction was cooled to room temperature, diluted with 10 ml saline, and acidified with dilute acetic acid with good stirring. A white precipitate formed which became granular with stirring. The product was isolated on a flitted funnel, washed with water, and dried at 40° C. overnight to yield 29.2 mg (89% yield) product as a white powder. LC/MS (FA) ES+ 385/387/389. 1H NMR (400 MHz, DMSO) δ 12.73-12.44 (br s, 1H), 7.36-7.24 (m, 4H), 4.26-4.18 (s, 2H), 3.74-3.63 (t, J=4.8 Hz, 4H), 3.49-3.39 (t, J=4.7 Hz, 4H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC.CCOC(C)=O>[O:7]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)COc2ccccc2)cc1

Procedure:
To a solution of phenol (9.4 g) and 2-bromo-1-(4-(methylthio)phenyl)ethanone (12.5 g) in 500 mL of acetone was added K2CO3 (13.8 g). The mixture was refluxed for 12 h, then diluted with 500 mL of 1:1 hexane/EtOAc. The solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in Et2O (500 mL), washed with 1N NaOH (100 ml) and dried over MgSO4. After filtration and concentration, the title compound (9 g) was collected by filtration and air dried.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:23](O)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (3.0 g, 0.014 mol) in THF (50 mL) at 0° C. was added DMF (0.1 mL) and oxalyl chloride (1.5 mL, 0.018 mol). The mixture was stirred at 0° C. for 1 h and then warmed to rt. The solvent was removed under reduced pressure. The obtained acid chloride was added to a mixture of tert-butyl alcohol (5.0 g, 0.067 mol), pyridine (10 mL), and CH2Cl2 (50 mL) at 0° C. The mixture was stirred at rt for 3 h, and then at 50° C. overnight. The mixture was washed with water, 2 N NaOH, and brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by column to give a colorless oil (1.5 g, 45%).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:16]([C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=1[CH:25]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:16]([C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:24]=1[CH2:25][NH:15][C@H:14]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2ccccc2)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of Compound 1 (150 mg, 0.60 mmol) and Compound 6 (160 mg, 0.60 mmol) in dry CH2Cl2 (6 ml) was added NaBH(OAc)3 (179 mg, 0.84 mmol) portionwise under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 3 hr. This was basified with sat. NaHCO3 aq., extracted with CH2Cl2, dried with MgSO4, and concentrated to give crude (2S,3S)-3-(2-phenoxy-5-(trifluoromethyl)benzyl)amino2-phenylpiperidine as a yellow oil. This was purified with chromatography to give pure (2S,3S)-3-(2-phenoxy-5-(trifluoromethyl)benzyl)amino-2-phenylpiperidine as a yellow oil (135 mg). This was diluted with ethyl acetate, added HCI-MeOH, and concentrated. The white solid was recrystallized from MeOH-ether to give Compound 7 as a white crystalline (108 mg, 36.0%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]2[CH2:9][CH2:10][CH:5]([CH:6]=[CH:7]2)[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:2]>[Pd].C(OCC)(=O)C>[CH:1]([C:3]1[CH:8]2[CH2:9][CH2:10][CH:5]([CH2:6][CH2:7]2)[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:2]
Reactant: O=CC1=C(c2ccccc2)C2C=CC1CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=CC1=C(c2ccccc2)C2CCC1CC2

Procedure:
3-Formyl-2-phenylbicyclo[2,2,2]octa-2,5-diene (3.7 g; 0.018 m) 5% Palladium on charcoal (0.3 g) and ethyl acetate (100 ml) were hydrogenated for 1 week. The catalyst was filtered off and the filtrate evaporated, then the residue distilled twice; Yield 1.9 g (51%) b.p. 160° C. at 0.2 mm/Hg.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([NH2:17])[CH:19]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Nc1cccc(O)c1
Product: Nc1cccc(Oc2ccc(C(=O)c3ccc(Oc4cccc(N)c4)cc3)cc2)c1

Procedure:
4,4'-bis(m-aminophenoxy)benzophenone was prepared in accordance with the method of Example 1 employing 4,4'-dichlorobenzophenone and m-aminophenol as the starting materials. 26% yield of product having a melting point of about 138°-140° C. was obtained.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8]([CH3:10])([CH3:9])[C@H:7]([CH:11]=O)[C:6]([CH3:13])=[CH:5][CH2:4]1)[CH3:2].[CH3:14][C:15]([CH3:17])=[O:16].CO[Na].CC(=O)C=C>C(O)C.CO>[CH2:1]([C@H:3]1[C:8]([CH3:10])([CH3:9])[C:7](/[CH:11]=[CH:14]/[C:15](=[O:16])[CH3:17])=[C:6]([CH3:13])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC=C(C)[C@@H](C=O)C1(C)C
Reactant: CC(C)=O
Agent: C=CC(C)=O
Agent: CO[Na]
Solvent: CCO
Solvent: CO
Product: CC[C@@H]1CCC(C)=C(/C=C/C(C)=O)C1(C)C
Reaction time: 65 h

Procedure:
This compound was prepared by aldol condensation of 2 g (0.011 mol) of (+)-(1R,5S)-5-ethyl-2,6,6-trimethyl-2-cyclohexen-1-carbaldehyde (obtained according to example 4i.) with 2 ml (0.03 mol) of acetone, in 10 ml of ethanol. After adding 0.1 ml of a 30% solution of CH3ONa in methanol, the reaction was allowed to proceed for about 65 h. Following the usual treatment, 1.3 g of 95% pure mixture were obtained, containing 83% of the above-mentioned butenone, 13% of its α-trans isomer and 4% of its α-cis isomer.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[C:13](Cl)(=[O:15])[CH3:14]>CC#N>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CC(=O)Cl
Solvent: CC#N
Product: CC(=O)n1ccc2ccc(N)cc21

Procedure:
1-(6-Amino-indol-1-yl)-ethanone (B-3) was synthesized following the general scheme above starting from 6-nitroindole and acetyl chloride. Overall yield (˜40%). HPLC ret. time 0.54 min, 10-99% CH3CN, 5 min run; ESI-MS 175.1 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][C:29]#[N:30])=[O:27])=[CH:21][CH:20]=3)[C:11]3S[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.O[O:32][S:33]([O-:35])=O.[K+].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:28][C:29]#[N:30])=[O:27])=[CH:23][CH:24]=3)[C:11]3[S:33](=[O:35])(=[O:32])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 18-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide (19 mg, 0.044 mmol, 1 eq.), oxone (55 mg, 0.18 mmol, 4 eq.), THF (3 ml) and water (3 ml). The clear solution was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was treated with sodium bicarbonate solution. Solid was collected by filtration and washed with water. After drying, the title compound was obtained as a white solid (11 mg, 53% yield). MW=467.93. 1H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.61 (t, J=4.8 Hz, 2H), 3.56 (s, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][C:5]2[N:6]=[C:7]([C:9]3[N:10](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:13][CH:12]=4)[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][C:5]2[N:6]=[C:7]([C:9]3[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:13][CH:12]=4)[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc3cc(C=C4SC(=O)NC4=O)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)C(=Cc2ccc3[nH]c(-c4nc5cc(Cl)c(Cl)cc5[nH]4)cc3c2)S1
Yield: 17.9 %

Procedure:
To a suspension of 5,6-dichloro-2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-1-(4-methylphenyl)sulfonylindol-2-yl]benzimidazole (77 mg, 0.13 mmol) in methanol (5 mL) was added aqueous sodium hydroxide (2 mol/L; 1 mL), and the mixture was heated to reflux for 19 h. The reaction mixture was cooled on an ice bath, and pH was adjusted to 7. The precipitated products were collected by filtration followed by trituration with tetrahydrofuran/ethyl acetate to afford 5,6-dichloro-2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]indol-2-yl]benzimidazole (10 mg, 18%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)([O-])=O>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1-c1ccccc1N
Reaction time: 3.5 h
Yield: 100 %

Procedure:
Compound 9H was synthesized by an adaptation of a literature procedure, Gillespie et al. (2002) J. Org. Chem. 67:3450-3458. 2,2′-Dinitrobiphenyl (102.0 g, 417.5 mmol) and 10% Pd/C (16.4 g) were combined with 300 mL EtOAc in a hydrogenation vessel. The vessel was pressurized to 40 psi H2 for 3.5 h (when H2 was no longer being consumed). The slurry was filtered through a plug of celite. Rotary evaporation followed by drying on a vacuum line gave pure product as light yellow/orange powder in 100% yield. 1H NMR (CDCl3, 297K, 300 MHz): δ 3.71 (s, 4H), δ 6.79 (dd, 2H, J=8.0, 1.2 Hz), δ 6.84 (td, 2H, J=7.4, 1.2 Hz), δ 7.12 (dd, 2H, J=8.0, 1.5 Hz), δ 7.19 (td, 2H, J=7.4, 1.5 Hz). 13C NMR (CDCl3, 297K, 300 MHz): δ 115.58, δ 118.71, δ 124.62, δ 128.81, δ 131.08, δ 144.22. HRMS (ESI-EMM): m/z=185.1073 ([M+H]+), Δ=2.7 ppm.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]2[S:22][C:23]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=2)[CH2:16]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[S:22][C:23]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=3)[CH2:16]2)=[O:11])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)cn1
Reactant: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)N[C@@H]2CCCN(c3nc(C(N)=O)c(Nc4ccccn4)s3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 6-tert-butylnicotinic acid (23.5 mg, 131 μmol) and 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide (38 mg, 119 μmol) in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (35 μL, 200 μmol) followed by 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 161 μmol). After stirring at ambient temperature overnight under an atmosphere of argon the reaction was quenched by the addition of saturated aqueous ammonium chloride (2 mL), the mixture poured into water (5 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were washed with brine (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a yellow solid. The crude product was purified by chromatography using a 13 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo and the residue lyophilized from acetonitrile/water to give (R)-2-(3-(6-tert-butylnicotinamido)piperidin-1-yl)-5-(pyridin-2-ylamino)thiazole-4-carboxamide as a pale yellow solid (37.8 mg, 66%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].C([O-])(O)=O.[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)(Cl)Cl>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:2][C:3](=[O:4])[NH:16][C:11]=2[CH:10]=1)([O-:8])=[O:7]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
At 0° C., chloroacetyl chloride (8.75 mL, 0.11 mol) was added dropwise to a mixture of 4-nitro-2-aminophenol (15.4 g, 0.1 mol), benzyltrimethylammonium chloride (18.6 g, 0.1 mol) and NaHCO3 (42 g, 0.5 mol) in chloroform (350 ml) over a period of 30 min. After addition, the reaction mixture was stirred at 0° C. for 1 h, then at 50° C. overnight. The solvent was removed under reduced pressure and the residue was treated with water (50 ml). The solid was collected via filtration, washed with water and recrystallized from ethanol to provide 6-nitro-4H-benzo[1,4]oxazin-3-one as a pale yellow solid (8 g, 41%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][N:20]=[C:21]4[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:24][C:22]4=3)[C:17](=[O:35])[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(Cl)(Cl)Cl.CO>CO.[C].[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][N:20]=[C:21]4[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:25]=[CH:24][C:22]4=3)[C:17](=[O:35])[CH:16]=[CH:15]2)[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCNCC3)c12
Yield: 68 %

Procedure:
1-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (341 mg, 0.697 mmol) in methanol was stirred with 5% palladium-carbon (500 mg) for one day under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: chloroform/methanol=9/1/(v/v)) to give the title compound (189 mg, yield 68%).