Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1.O>CN(C)C=O>[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=3)[N:11]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: FC(F)(F)c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(Cn2nc(-c3ccccc3)c3ccc(C(F)(F)F)cc32)n1
Reaction time: 0.08 h
Yield: 10.9 %

Procedure:
Sodium hydride (added with 40% mineral oil, 20 mg, manufacture by Kanto Chemical Co., Inc.) was added to a solution of 3-phenyl-6-(trifluoromethyl)-1H-indazole (40 mg), which had been synthesized in Reference Example 18 according to the methods of Reference Examples 8 and 9, in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, ethyl 2-bromomethylthiazole-4-carboxylate (114 mg) synthesized according to the method of the literature (K. Benno, et al., Liebigs. Ann. Chem., 1981, 4, 623-632) was added thereto, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 7.2 mg of the title compound. LC-MS: HPLC retention time 1.41 minutes, m/z 404 (M+H), condition C-1.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15](=[O:17])[C:16]=3[N:8]2[CH:7]=[C:6]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].[N+:26]([O-])([OH:28])=[O:27].O>C(O)(=O)C.CO>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15](=[O:17])[C:16]=3[N:8]2[C:7]([N+:26]([O-:28])=[O:27])=[C:6]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCn1c(-c2ccccc2)cn2c3c(=O)[nH]c(=O)n(C)c3nc12
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCCn1c(-c2ccccc2)c([N+](=O)[O-])n2c3c(=O)[nH]c(=O)n(C)c3nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
To a solution of commercially available 8-butyl-1-methyl-7-phenyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (3, 100 mg, 0.296 mmol) in acetic acid (500 μL) was added HNO3 (fuming, 24 μL, 0.592 mmol), and the resulting mixture was stirred at room temperature for 12 h. Water was added, and the resulting precipitate was filtered off. Cristallization in methanol afforded the desired product as a yellow solid (26 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ=11.05 (s, 1H), 7.60-7.69 (m, 5H), 3.93 (t, J=7.3 Hz, 2H), 3.43 (s, 3H), 1.62 (quint, J=7.3 Hz, 2H), 1.14 (sext, J=7.3 Hz, 2H), 0.70 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ=153.4, 152.1, 150.5, 144.6, 134.4, 130.9, 130.7, 128.5, 126.9, 124.7, 101.6, 44.3, 29.5, 29.0, 18.6, 12.9; IR (film) ν=3172, 3052, 2964, 1693, 1502, 1356, 1294, 732, 577 cm−1; HRMS (ESI): m/z: calcd for C18H18N6O4Na+: 405.1287, found: 405.1288.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].O.Cl.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH:18]=1)#[N:4]
Reactant: O=C1CCNCC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 8.8 gm (157 mMol) potassium hydroxide in 85 mL methanol were added 8.15 gm (57.33 mMol) 5-cyano-1H-indole and 7.86 gm (51.17 mMol) 4-piperidone hydrochloride monohydrate. The resulting mixture was heated to reflux for 48 hours and was then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure to about half volume and was then treated with 1M HCl until the pH of the solution was between 1 and 2. The resulting solution was extracted twice with 100 mL of diethyl ether and the remaining aqueous phase was treated with 5N sodium hydroxide until the pH of the solution was between 12 and 14. This aqueous phase was extracted 5 times with 10% methanol in dichloromethane. These organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to a residue. This residue was subjected to flash silica gel chromatography, eluting with dichloromethane which contained 20% methanol and 2% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 6.86 gm (60%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9]C=CC=1C(Cl)=O.[CH2:11]([N:13](CC)CC)C.CN.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:21]=[CH:22][C:23]([C:24]([NH:13][CH3:11])=[O:20])=[CH:9][N:10]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCN(CC)CC
Agent: CN
Product: CNC(=O)c1ccc(Cl)nc1
Yield: 92 %

Procedure:
2-Chloronicotinoyl chloride (5.65 g, 32.1 mol) was dissolved in tetrahydrofuran (64 mL), added triethylamine (5.59 mL, 40.1 mol), and a solution of methylamine in tetrahydrofuran (20.1 mL, 40.1 mol) sequentially under ice-cold conditions, and stirred at room temperature for 3.5 hours. The reaction solution was concentrated in vacuo, recrystallized (ethyl acetate/hexane). The title compound (5.06 g (yield 92%)) was obtained as a light brown crystal.
Reaction SMILES: [Sb:1](Cl)(Cl)Cl.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Sb]>C1(C)C=CC=CC=1.O>[C:5]1([CH3:15])[CH:6]=[CH:7][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:9][CH:10]=1.[C:17]1([CH3:27])[CH:18]=[CH:19][C:20]([S:23]([O-:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1.[C:5]1([CH3:15])[CH:6]=[CH:7][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:9][CH:10]=1.[Sb+3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cl[Sb](Cl)Cl
Agent: [Sb]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: [Sb+3]
Reaction time: 2 h

Procedure:
This compound was prepared by a double decomposition reaction between antimony trichloride and p-toluene sulfonic acid. A solution of 28.53 g (0.15 mole) of p-toluene sulfonic acid monohydrate in 150 cc of toluene was distilled until the water was removed. The anhydrous acid solution was then added dropwise to a solution of 11.4 g (0.05 moles) of antimony trichloride in about 50 cc of refluxing toluene. The solution became dark reddish brown, and the initially formed precipitate redissolved. Reflux continued for two hours, and the solution was then cooled. It contained 3.05 wt% antimony by calculation. Part of the solution was used to treat a catalyst for testing, as outlined below.
Reaction SMILES: O[C@H:2]1[C@H:9]2[C@H](O[C:7]([CH3:11])(C)[O:8]2)O[C@H]1C(O)=O.C[N:16]([C:18]([O:22]N1N=NC2C=CC=CC1=2)=[N+:19](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.N1CCOCC1>C1COCC1>[N:16]1([C:18]([NH2:19])=[O:22])[CH2:11][CH2:7][O:8][CH2:9][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: NC(=O)N1CCOCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 134.9 %

Procedure:
To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0 g, 24.5 mmol) in THF (100 mL, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20° C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20° C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:33])/[C:19](=[N:25]\[O:26][CH2:27][C:28](=[O:32])[NH:29][O:30][CH3:31])/[C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:41]([O:44][CH2:45]I)(=[O:43])[CH3:42].Cl>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:33])/[C:19](=[N:25]\[O:26][CH2:27][C:28](=[O:32])[NH:29][O:30][CH3:31])/[C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([O:14][CH2:45][O:44][C:41](=[O:43])[CH3:42])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCI
Reactant: CONC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CONC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(C)=O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Reaction time: 1 h

Procedure:
(6R,7R)-3-Acetoxymethyl-7-[Z-2-methoxycarbamoylmethoxyimino-2-(fur-2-yl)acetamido]-ceph-3-em-4-carboxylic acid (992 mg) was dissolved in dry N,N-dimethylformamide (8 ml). Dried potassium carbonate (138 mg) was added and the mixture was stirred at 0°. Iodomethyl acetate (1.1 g) in a little dimethylformamide was added, stirring was continued at 0° for 1 hr, and the mixture was poured into hydrochloric acid (N, 50 ml) and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were washed with N-hydrochloric acid (2×50 ml), water (100 ml) and saturated sodium hydrogen carbonate solution (2×30 ml), dried (Na2SO4) and evaporated. The residue in a little ethyl acetate was added dropwise to well-stirred light petroleum (b.p. 40°-60°), when the ester separated as an off-white powder, 513 mg, λmax (EtOH) 277.5 nm, νmax (Nujol) 3240 (--NH), 1786 (β-lactam), 1765, 1742 (acetate+--CO2CH2OCOCH3), 1680, 1540 cm-1 (--CONH--), τ(DMSOd6) 6.25 (--OCH3, 2--CH2 --), 5.38 (--O--CH2 --CO--), 2.01, 3.11, 3.22 (fur-2-yl), 0.18 (--CONH--), 4.05 (7H), 4.69 (6H), 4.99, 5.25 (3--CH2 --), 7.86, 7.96 (--COCH3), 4.09 (--OCH2O--).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>O>[N:6]1([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 250-mL round-bottomed flask was charged with a solution of NaHCO3 (10.7 g, 127.38 mmol, 2.00 equiv) in H2O (80 mL), ethyl piperidine-3-carboxylate (10 g, 63.69 mmol, 1.00 equiv) and benzyl carbonochloridate (11.9 g, 70.00 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The progress was monitored by TLC (EtOAc: PE=1:5). Upon completion, the resulting solution was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:100) afford 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate as pale yellow oil (11.4 g, (62%).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[OH2:13].[C:14]1(C)C=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=1.[Cl-].[Na+]>ClCCl.O1C=CCCC1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: O
Reactant: C#CCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCCCCCCCCCOC1CCCCO1
Reaction time: 8 h
Yield: 92 %

Procedure:
17.5 g (0,104 mol) of undec-10-yn-1-ol were dissolved in 100 ml of dichloromethane and 25 ml of dihydropyran, and a catalytic amount (spatula tipful) of p-toluenesulfonic acid monohydrate was added. The reaction mixture was left to stand overnight at room temperature and poured into saturated aqueous sodium chloride solution. Extraction with dichloromethane (3×), drying (Na2SO4) of the combined organic phases and flash chromatography on silica gel (n-heptane/ethyl acetate=10:1) gave 24 g (92% of theory) of 11-tetrahydropyranyloxyundecyne.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:6][N:7]2[CH2:16][C:17]([OH:19])=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>O.CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:6][N:7]2[CH2:16][C:17]([NH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:19]
Reactant: NCCN1CCOCC1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)O)c12
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 25 °C
Reaction time: 23 h
Yield: 76.6 %

Procedure:
To a DMF solution (2 ml) of [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid (800 mg, 2.07 mmol) were sequentially added a DMF solution (1 ml) of 4-(2-aminoethyl)morpholine (273 mg), triethylamine (506 mg, 5.0 mmol), diethylphosphorocyanidate (DEPC, 405 mg, 2.48 mmol) and DMF (1 ml) while ice-cooling, followed by stirring at room temperature for 23 hours. Water was added to the reaction mixture and then subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (789 mg, yield: 77%).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[CH:6]([CH:8]=[O:9])=[O:7]>>[OH:7][CH:6]1[CH:8]([OH:9])[O:4][CH:2]([CH3:3])[CH2:1][O:5]1
Reactant: O=CC=O
Reactant: CC(O)CO
Product: CC1COC(O)C(O)O1
Yield: 93 %

Procedure:
1 mol of 1,2-propanediol is stirred with 40% strength by weight aqueous glyoxal solution at 50° C. for 3 hours. Water is then distilled off at 70° C. and 100 mbar, leaving 125 g (93% of theory) of 2,3-dihydroxy-5-methyl-1,4-dioxane in the form of a clear, colorless oil which crystallizes on prolonged standing.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>>[NH2:26][C:22]1[O:1][C:2]2[C:10]([CH:16]([C:15]3[CH:14]=[C:13]([F:12])[CH:20]=[C:19]([F:21])[CH:18]=3)[C:23]=1[C:24]#[N:25])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: Cn1ccc2c(O)cccc21
Reactant: N#CCC#N
Reactant: O=Cc1cc(F)cc(F)c1
Product: Cn1ccc2c3c(ccc21)C(c1cc(F)cc(F)c1)C(C#N)=C(N)O3

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 3,5-difluorobenzaldehyde (38 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 38 mg (42%) of white solids. 1H NMR (CDCl3): 7.07-7.03 (m, 2H), 6.76-6.73 (m, 3H), 6.68-6.62 (m, 1H), 6.57 (d, J=3.0 Hz, 1H), 4.83 (s, 1H), 4.72 (brs, 2H), 3.78 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([NH2:13])=[C:4]([Cl:14])[CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][N:43]([C:20](=[O:21])[NH:13][C:5]3[CH:6]=[C:7]([O:8][C:9]([F:11])([F:12])[F:10])[C:2]([Br:1])=[CH:3][C:4]=3[Cl:14])[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(OC(F)(F)F)c(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3cc(OC(F)(F)F)c(Br)cc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 4-bromo-2-chloro-5-trifluoromethoxy-phenylamine (0.55 g, 1.90 mmol) in DCM (4.9 mL) was added CDI (0.34 g, 2.09 mmol). The reaction solution was stirred at RT overnight and then 4-piperazin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (0.56 g, 2.09 mmol; Preparation 12) was added and the reaction mixture was stirred for 30 min at RT, concentrated under vacuum and purified by silica gel chromatography (0-5% MeOH/DCM). Pure fractions were combined and concentrated under vacuum to provide the title intermediate (0.67 g, 60% yield) as a white foam. (m/z): [M+H]+ calcd for C22H29BrClF3N4O4 585.1 found 584.6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][OH:53]>CN(C)C=O>[OH:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[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: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (20 g, 111.11 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), HATU (63.2 g, 166.32 mmol, 1.50 equiv), N,N-diisopropylethylamine (21.5 g, 166.67 mmol, 1.50 equiv), 2-(2-aminoethoxy)ethanol (23.3 g, 221.90 mmol, 2.00 equiv). The resulting solution was stirred for overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 10×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (100:1). This resulted in 15 g (51%) of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate as red oil.
Reaction SMILES: Br[CH:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C:3]1=[O:9].Cl.[C:11]([C:14]1[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[NH:13])[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:9][C:3]12[CH2:4][CH:5]([O:7][CH3:8])[CH2:6][CH:2]1[NH:13][C:11]([C:14]1[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])=[N:12]2
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Reactant: COC1CC(=O)C(Br)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C2=NC3(O)CC(OC)CC3N2)c(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Into around-bottom flask, was placed a solution of 2-bromo-4-methoxycyclopentanone (compound 461.4, 600 mg, 1.86 mmol, 60%) in ACN (15 mL). Methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 320 mg) and potassium carbonate (430 mg, 3.11 mmol) were added and the mixture was stirred overnight at 80° C. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 mL) and then washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) as the eluent to obtain the title compound as a brown oil (200 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[N:13]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:16]1[CH2:17][CH2:18][CH2:19][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccnc3ccc(Br)cc23)CC1

Procedure:
6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted with tert-butyl 1,4-diazepane-1-carboxylate (3.7 g, 18.8 mmol) and K2CO3 (4 g, 29 mmol) in DMSO at 100° C. overnight. After cooling the mixture was poured into water and extracted with DCM. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc:hexane 1:1 to 2:1 giving 2.1 g (36%) of yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (d, J=5.5 Hz, 9H) 2.08-2.16 (m, 2H) 3.35-3.44 (m, 4H) 3.60-3-73 (m, 4H) 6.87 (d, J=5.5 Hz, 1H) 7.69 (dd, J=9.0, 2.0 Hz, 1H) 7.88 (d, J=8.5 Hz, 1H) 8.16 (s, 1H) 8.65 (d, J=5.0 Hz, 1H). MS (ESI+) for C19H24BrN3O2 m/z 406.4 (M+H)+. HRMS (EI) calcd for C19H24BrN3: 405.1052, found 405.1045.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]=[C:9]=[O:10])=[O:7])([O-:3])=[O:2].[Br:15][C:16]1[CH:17]=[N:18][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[N:20][CH:21]=1>O1CCOCC1.O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([S:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])=[O:10])=[CH:27][CH:28]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc(Sc2ncc(Br)cn2)cc1
Reactant: O=C=NC(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-nitrobenzoyl isocyanate (3 g, 0.016 mol) in dry 1,4-dioxane (15 mL) was added dropwise to a solution of 4n (2.93 g, 0.01 mol) in dry 1,4-dioxane (15 mL) with stirring at room temperature. The reaction mixture was stirred for 18 hours and then diluted with water. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, and the organic layer was washed with water 2-3 times, dried, and concentrated to give 1-[4-(5-bromopyrimidin-2-ylsulfanyl)-phenyl]-3-(2-nitrobenzoyl)urea (6n), yield 92%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.35 (br, s, 1H), 8.78 (s, 2H), 8.22 (m, 1H), 7.91 (m, 1H), 7.77 (m, 2H), 7.67 (m, 2H), 7.57 (m 2H); EI-MS m/z 473 [M]+, 475 [M+2]+; HRMS calculated for C18H12BrN5O4SNa [M+Na]+:495.9685, found: 495.9701. Anal. (C18H12BrN5O4S) C, H, N.