Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[BrH:26].S(=O)(=O)(O)O>O>[C:1]([C:5]([C:8]([C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:26])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: Br
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 19.52 g of CF3(CF2)3(CH2)10CH2OH and 200 mL of 48 weight percent aqueous hydrobromic acid was slowly added 20 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 24 hr, and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to an amber liquid, which was eluted through 3 inches of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 19.82 g of CF3(CF2)3(CH2)10CH2Br as a clear, colorless liquid, b.p. 120-170° C. at 0.06 torr (8 Pa).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCCN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Morpholin-4-yl-ethylamine (0.18 mL, 1.44 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.5 g, 1.2 mmol) in dry DMF (1 mL). The reaction mixture was then stirred at 120° C. for 3 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution (10 mL), and refluxed at 70° C. for 3 h. The reaction mixture was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.150 g, (24.19%); 1H NMR (DMSO-d6): δ 2.40 (t, 4H, 2CH2), 2.50-2.60 (m, 4H, 2CH2), 3.10 (m, 4H, 2CH2), 3.15-3.20 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.50 (t, 1H, NH), 5.15 (s, 2H, CH2), 6.10 (t, 1H, NH), 6.7 (s, 2H, 2Ar), 8.10 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (EI+) 524 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:23]([OH:26])[CH2:24][CH3:25]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10](=[O:15])[N:11]([CH2:25][CH2:24][CH2:23][OH:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: CCC(O)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c(OCc2ccccc2)cccn1CCCO
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To the solution of Compound 6 (0.202 g, 1 mmol) in acetonitrile was added K2CO3 (2 equiv.) followed by iodopropanol (0.186 g, 1 mmol). The reaction mixture was stirred at 65° C. overnight. On completion of the reaction, the reaction mixture was filtered and solvent was evaporated under vacuum. The residue was dissolved in water and extracted three times with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuum. The resulting compound 12 was purified by column chromatography (2:100, CH3OH/CH2Cl2). Yield: (85%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[C:5]([NH2:25])=[C:4]([NH2:26])[N:3]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:25]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=3)[NH:26]2)=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: Nc1nc(N)c(N)c(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)n1
Reactant: O=Cc1ccc(Br)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(Br)cc3)[nH]c2n1
Yield: 74 %

Procedure:
This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]pyrimidine and 4-bromobenzaldehyde in 74% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.009 g of product in 39% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:18][C@@H:19]([CH3:31])[CH2:20][C@H:21]([CH3:30])[O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:18][C@@H:19]([CH3:31])[CH2:20][C@H:21]([CH3:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(O)cc1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.50 g of 4-(4'-methoxyphenyl)benzoic acid, 0.44 g of (S,S)-4-(3'-chloro-1'-methylbutoxy)phenol, 0.45 g of dicyclohexylcarbodiimide, 0.05 g of 4-pyrrolidinopyridine and 20 ml of methylene chloride were stirred together at room temperature for five hours. The crude product obtained in the same manner as the one described in Example 8 was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (85:15) as a developing solvent and recrystallized from ethyl alcohol to thereby give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH2:19]([O:18][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1)[CH3:20]
Reactant: CCOC(=O)C(C)C
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc(CC(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of diisopropylamine (13.11 mmol, 1.8 mL) in anhydrous tetrahydrofuran (40 mL) cooled to −78° C. under a nitrogen atmosphere was added 2.5M n-BuLi in hexanes (13.11 mmol, 5.24 mL). The resulting solution was allowed to stir at −78° C. for 20 minutes, warmed to room temperature for 10 minutes, then cooled back to −78° C. for 10 minutes. The mixture was added to a solution of ethyl isobutyrate (13.11 mmol, 1.76 mL) dissolved in anhydrous tetrahydrofuran (20 mL) cooled to −78° C. The resulting solution was allowed to stir at −78° C. for 1 h. (4-Bromomethyl-phenyl)-acetic acid (1 g, 4.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the solution dropwise. The solution was warmed to room temperature and was allowed to stir for 20 minutes. The reaction mixture was poured over a dilute HCl solution (1 N). The aqueous layer was isolated and extracted with diethyl ether (1×). The organic layers were combined, washed with 2N HCl (2×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to a crude oil. The oil was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 10% methanol/methylene chloride to give 3-(4-carboxymethyl-phenyl)-2,2-dimethyl-propionic acid ethyl ester as a white solid (0.97 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:6]
Reactant: C1COCCN1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)N5CCOCC5)c(F)c4)c3c2)o1
Yield: 78 %

Procedure:
In the same manner as in Example 117 and using 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and using morpholine instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 78%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH3:41]CN(C(C)C)C(C)C.CI>C(Cl)(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[N:20]([CH3:41])[CH:21]=[C:22]([CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:37]([F:40])([F:38])[F:39]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)c2ccccc21
Agent: [Br-]
Agent: [Zn+2]
Solvent: CI
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2cn(C)c3ccccc23)c(=O)nc1SCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#N)c1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-[({5-[(1-methyl-1H-indol-3-yl)methyl]-4-oxo-1,4-dihydro-2-pyrimidinyl}thio)methyl]benzonitrile (60 mg, 0.103 mmol), DIPEA (0.054 mL, 0.310 mmol) and zinc bromide (23.26 mg, 0.103 mmol) in chloroform (2 mL) was added MeI (0.013 mL, 0.207 mmol). The mixture was heated at 60° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (8.3 mg, 13.51% yield). LCMS: rt=3.78 min, [M+H+]=595
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:15])C=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].I([O-])(=O)(=O)=O.[Na+]>O.C(OCC)C>[OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(CC(=O)C=O)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1ccc(CC=O)cc1
Reaction time: 2 h

Procedure:
A biphasic mixture of 3-[4-(1-hydroxy-1-methylethyl)phenyl]propane-1,2-dial (5.44 g, 25.9 mmol) in water (85 mL) and diethyl ether (170 mL) was charged with sodium periodate (11.07 g, 51.7 mmol) and stirred vigorously for two hours. The reaction mixture was then partitioned between diethyl ether (50 mL) and saturated aqueous sodium thiosulfate (50 mL), and the layers were separated. The aqueous layer was extracted with diethyl ether (2×100 mL), and the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. To remove water left over, the concentrated material was dissolved in dichloromethane (70 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:22])[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19](=[O:20])[C:14]2[N:15]=[C:16]([CH3:18])[S:17][C:13]=2[C:12](=[O:21])[CH:11]=1.CO[C:25]1[C:44](=[O:45])[C:29]2[N:30]=[C:31]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)=[O:34])[S:32][C:28]=2[C:27](=[O:46])[CH:26]=1>C(O)C>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([NH:35][C:33]([C:31]2[S:32][C:28]3[C:27](=[O:46])[CH:26]=[C:25]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:22])[CH2:6][CH2:7][CH2:8][NH:9][C:10]4[C:19](=[O:20])[C:14]5[N:15]=[C:16]([CH3:18])[S:17][C:13]=5[C:12](=[O:21])[CH:11]=4)[C:44](=[O:45])[C:29]=3[N:30]=2)=[O:34])=[CH:41][CH:40]=1
Reactant: COC1=CC(=O)c2sc(C(=O)Nc3ccc(OC)cc3)nc2C1=O
Reactant: Cc1nc2c(s1)C(=O)C=C(NCCCN(C)CCCN)C2=O
Solvent: CCO
Product: COc1ccc(NC(=O)c2nc3c(s2)C(=O)C=C(NCCCN(C)CCCNC2=CC(=O)c4sc(C)nc4C2=O)C3=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 9 %

Procedure:
5-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione is solubilized in 250 ml of ethanol and 2.12 g (6.16 mmol; 0.8 equivalent) of 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide is added. The reaction mixture is maintained under stirring at 60° C. for 4 hours, then the solvent is evaporated off under reduced pressure. The residue is then purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5) and 450 mg (yield=9%) of N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide is obtained in the form of red powder.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30]>>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[C:31]1[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:17][CH:18]=1)=[O:30]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCO)c1cc2ccccc2[nH]1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2cc3ccccc3[nH]2)cc1
Yield: 91 %

Procedure:
The product of Example 2 (0.27 g, 0.83 mmol) was coupled to N-(3-hydroxypropyl)-1H-indole-2-carboxamide, prepared according to Example 18, (0.20 g, 0.91 mmol) using the procedure of Example 3 to provide 0.4 g (91% yield) of yellow solid powder. MP 199° C.; 1H NMR (DMSO-d6): δ1.9 (s, CH3), 2.0-2.1 (m, CH2), 3.20 (s, CH3), 3.32-3.51 (m, CH2, CH2), 6.8-7.2 (m, 8 Ar H), 7.36 (d, 1 Ar H), 7.58 (d, 1 Ar H), 7.78 (d, 1 Ar H), 7.93 (s, 1 NH), 8.52 (s, NH), 12.0 (s, 0H). Electrospray Mass Spec: m/z 522.2 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(O)(C)(C)C.[K]>O1CCCC1.C(O)(C)(C)C.O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: C=CC(=O)OCC
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)CCN1C(=O)C(N=[N+]=[N-])CCc2ccccc21

Procedure:
A solution of 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepine-2-one [prepared as described by Watthey et al., J. Med. Chem., 28, p. 1511-15156 (1985)] in tetrahydrofuran/tert-butanol was cooled to 0° C. and treated with ethyl acrylate and 1N tert-butanol, potassium salt/tetrahydrofuran according to the procedure of Example 40 part (a) affording 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-propanoic acid, ethyl ester as a syrup. TLC (ethyl ether:hexane, 1:1) Rf =0.45.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(CBr)ccc1Cl
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a stirred solution of 2-chloro-5-methyl-benzoic acid (25 g) in chloroform (500 ml) at 50° C. was added N-bromosuccinimide (27.40 g). The flask was purged with nitrogen and azobisisobutyronitrile (0.10 g) added in one portion. The solution was heated at reflux for 1 h. Further azobisisobutyronitrile (0.10 g) was added and the mixture heated a further 3 h. The solution was concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ether solution was washed with 2N aqueous hydrochloric acid solution followed by brine then dried over magnesium sulphate. The solution was concentrated to a volume of 150 ml then diluted with isohexane. After further partial concentration crystallization started. The mixture was allowed to stand in an ice-bath for 1 h. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitled compound (17 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])/[C:5](/[O:18][CH:19]([CH3:21])[CH3:20])=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)[CH3:2].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH:19]([O:18]/[C:5](=[CH:6]\[C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([C:12]([NH:30][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)=[O:14])[CH:15]=1)/[C:4]([O:3][CH2:1][CH3:2])=[O:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)O)c1)OC(C)C
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
65 mg of 5-[(Z)-3-ethoxy-2-isopropoxy-3-oxo-1-propenyl]-2-methoxybenzoic acid and 37 mg of 4-(trifluoromethyl)benzylamine were dissolved in 1 ml N,N-dimethylformamide, and 33 μl diethyl cyanophosphonate and 30 μl triethylamine were added under ice-cooling. After stirring the reaction mixture at room temperature for 16 hours, it was poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 77 mg of ethyl (Z)-2-isopropoxy-3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2-propenoate was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:40]1[CH2:45][CH2:44][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:42][CH2:41]1.CCN(CC)CC>CN(C=O)C>[N:40]1([C:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[O:11])[CH2:41][CH2:42][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:44][CH2:45]1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OCC(F)(F)F)cc1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,2,2-Trifluoroethoxy)benzoic acid (22 mg, 0.10 mmol), HATU (42 mg, 0.11 mmol), and DMF (0.8 mL) were combined and allowed to stir at room temperature for 10 minutes. The activated acid was then added to spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (28 mg, 0.10 mmol) followed by the addition of Et3N (84 μL, 0.60 mmol). The reaction mixture was stirred at room temperature for 17 h before it was filtered and purified by prep-HPLC (5 mM HCl/H2O and MeOH) to provide spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(2,2,2-trifluoroethoxy)phenyl)methanone. ESI-MS m/z calc. 442.2, found 443.4 (M+1)+. Retention time: 2.05 minutes (4 min run).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:17][NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=1>C(Cl)Cl>[CH3:26][O:25][C:23]1[N:22]=[C:21]([O:27][CH3:28])[N:20]=[C:19]([N:18]([CH3:17])[C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:12])=[O:13])=[O:16])[N:24]=1
Reactant: CNc1nc(OC)nc(OC)n1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1nc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ccccc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 2-methylsulfonylbenzenesulfonylisocyanate (2.1 g, 8.0 mmol) in dry methylene chloride (12 ml) was added to 2-methylamino-4,6-dimethoxy-1,3,5-triazine (1.0 g, 6.0 mmol) and a catalytic amount of 1,4-diaza[2.2.2]bicyclooctane. The mixture was stirred at room temperature overnight. The solvent was removed in-vacuo and 1-chlorobutane was added to the residue. The precipitated solid was filtered and dried to give N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)(methyl)aminocarbonyl]-2-(methylsulfonyl)benzenesulfonamide (2.3 g) as a white powder, m.p. 160°-162.5°. The product showed characteristic singlets in the NMR at δ3.25 (NCH3), 3.40 (SO2CH3) and 4.0 (OCH3), and showed infrared absorption peaks at 1690, 1550, 1420, 1340, 1310 and 1150 cm-1.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:19]([C:24](O)=[O:25])#[C:20][C:21]([OH:23])=[O:22]>>[CH2:12]([N:11]1[C:24](=[O:25])[C:19](=[CH:20][C:21]([OH:23])=[O:22])[S:10][C:9]1=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCCNC(=S)NCCCCCCC
Product: CCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCC
Yield: 88.4 %

Procedure:
Prepared by the method described in Example 16 from N,N'-diheptylthiourea (18.0 g, 66 mmoles) and acetylenedicarboxylic acid (8.0 g, 66 mmoles). Recrystallization from acetonitrile gave the product (21.5 g), mp 80°-81° C.