Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[C:12]([CH3:15])[S:13][CH:14]=1.[NH4+].[Cl-]>CCOCC>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1
Reactant: Cc1cc(Br)cs1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(-c2ccccc2)cs1

Procedure:
A solution of PhMgBr (prepared from 1.65 g of Mg (0.0678 mol) and 10.64 g of PhBr (0.0678 mol) in 40 mL of diethyl ether) was added to a mixture of 10 g (0.0565 mol) of 4-bromo-2-methylthiophene and 0.62 g (0.0012 mol) of NiCl2dppp in 50 mL of ether under stirring at reflux. The reaction mixture was refluxed for additional 3 h and then stirred overnight. The resulting mixture was treated with 10% aqueous NH4Cl, the organic layer was separated, washed with 10% aqueous NH4Cl and then dried with anhydrous Na2SO4. Solvent was evaporated, the residue was recrystallized from methanol. Yield 6.8 g (70%) of colorless crystals.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:14][C:15]1[C:16]2[N:17]([CH:21]=[CH:22][N:23]=2)[CH:18]=[CH:19][CH:20]=1>Br.C(O)(=O)C>[N:23]1[CH:22]=[CH:21][N:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][S:1][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=4[N:3]=3)[C:16]=12
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: OCc1cccn2ccnc12
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(SCc3cccn4ccnc34)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2.92 g (23 mmole) of 3-hydroxymethyl-2-pyridinamine, 6.15 g (35 mmole) of chloroacetaldehyde, and 2.0 g (35 mmole) of sodium bicarbonate in 100 ml of ethanol was heated at reflux for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to a solid. Recrystallization from diethyl ether yielded 4.4 g of 8-hydroxymethylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra. A mixture of 683 mg (3.8 mmole) of 2-mercapto-5-methoxybenzimidazole and 700 mg (3.8 mmole) of 8-hydroxymethylimidazo[1,2-a]pyridine was dissolved in 3 ml of 30% hydrogen bromide in acetic acid and heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield the title compound as an oil. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([NH:5][NH2:6])=[O:4].[N+:12]([C:15]([N+:24]([O-:26])=[O:25])([N+:21]([O-:23])=[O:22])[CH2:16][CH2:17][C:18](Cl)=[O:19])([O-:14])=[O:13].Cl.C(=O)(O)[O-].[Na+]>C(OCC)C.N1C=CC=CC=1>[N+:12]([C:15]([N+:21]([O-:23])=[O:22])([N+:24]([O-:26])=[O:25])[CH2:16][CH2:17][C:18]([NH:6][NH:5][C:3](=[O:4])[C:2]([F:11])([F:1])[C:7]([F:8])([F:9])[F:10])=[O:19])([O-:14])=[O:13]
Reactant: NNC(=O)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)F
Reaction time: 0.08 h

Procedure:
A mixture formed by adding 0.77 g (0.0043 mole) of N-(perfluoropropionyl)hydrazine to a solution of 1.05 g (0.0043 mole) of 4,4,4-trinitrobutyryl chloride in 30 mL of anhydrous diethyl ether was stirred at 20° C during the dropwise addition of 0.35 mL of pyridine. After 5 minutes, dilute hydrochloric acid (10 mL) was added, and the ether layer was separated and dried (MgSO4). Removal of volatiles gave a semisolid which was stirred with dilute sodium bicarbonate to give 1.0 g, mp 105°-118° C. Crystallization from 1,2-dichloroethane gave the product, N-(4,4,4-trinitrobutyryl)-N'-(perfluoropropionyl)hydrazine, 0.65 g (41%), mp 123°-125° C.; 1H NMR (acetone-d6 +D2O): 2.95 (t, 2H); 3.85 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[NH2:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:13][C:12]2[C:11]([F:10])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=C(O)c1ccc(Br)o1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1c(F)cccc1F)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of 5-bromofuran-2-carboxylic acid acid (2.0 g, 10.4 mmol) in DMF (30 mL), 2,6-difluoroaniline (1.27 mL, 12.5 mmol), DIPEA (3.66 mL, 20.9 mmol) and HATU (4.78 g, 12.5 mmol) were successively added. The resulting mixture was stirred at RT for 3 h. The reaction mixture was diluted with ethyl acetate (50 mL) followed by water (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 20% ethyl acetate in hexane) to afford 400 mg (13%) of the title compound as white solid. 1HNMR (400 MHz, CDCl3) δ 7.57 (s, D2O exchangeable, 1H), 7.31-7.25 (m, 1H), 7.24 (d, J=3.5 Hz, 1H), 7.01 (t, J=7.5 Hz, 2H), 6.54 (d, J=3.5 Hz, 1H); ESI-MS (m/z) 302, 304 [(MH)+ Br79,81].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:15]4=[C:14]([CH3:31])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:34]([F:37])([F:36])[F:35])([CH3:3])[CH3:2].[Li+].[OH-]>CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]4=[C:14]([CH3:31])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:34]([F:37])([F:35])[F:36])([CH3:3])[CH3:2]
Reactant: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C(F)(F)F)c4)cc13)CCC2CC(=O)O
Temperature: 75 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.366 g, 0.707 mmol) in dioxanes was added aq LiOH (3.0 mmol). The reaction was stirred at 75° C. for 16 h, diluted with EtOAc and washed with 1 M HCl (aq), dried over MgSO4, filtered, and concentrated. The residue was triturated with hexanes to give the title compound as a solid (0.313 g). LCMS m/z=462.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 2.15 (s, 3H), 2.19-2.29 (m, 1H), 2.42-2.48 (m, 1H), 2.69-2.82 (m, 2H), 3.57-3.65 (m, 1H), 3.86-3.97 (m, 1H), 3.97-4.08 (m, 1H), 4.73-4.84 (m, 1H), 5.07 (s, 2H), 6.74 (dd, J=8.72, 2.40 Hz, 1H), 7.01 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H), 7.29 (d, J=9.22 Hz, 1H), 7.64-7.72 (m, 2H), 12.26 (bs, 1H).
Reaction SMILES: C([N:4]1[C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[C@H:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:7]2[CH:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:24][C:6]=2[C:5]1=[O:31])C=C>C(O)CC.[Rh](Cl)(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:8]2[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH:4][C:5](=[O:31])[C:6]3[S:24][C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:22][C:7]2=3)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: C=CCN1C(=O)c2sc(N3CCOCC3)cc2[C@@H](c2ccc(Cl)c(Cl)c2)[C@@H]1C(=O)OC
Agent: Cl[Rh](Cl)Cl
Solvent: CCCO
Product: COC(=O)[C@@H]1NC(=O)c2sc(N3CCOCC3)cc2[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Yield: 88.2 %

Procedure:
A mixture of methyl rel-(4R,5R)-6-allyl-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.344 g, 0.714 mmol) and rhodium(III)chloride, (22.2 mg, 0.106 mmol) in 1-propanol (9.0 mL) was heated in a sealed tube under argon at 120° C. for 50 h. The reaction mixture was evaporated and purified by silica gel chromatography to afford the product as a white solid (0.278 g, 88%). LCMS: (AA), ES+: 441, 443, 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.3 Hz, 1H), 7.34-7.25 (m, 1H), 7.04 (dd, J=8.3, 2.0 Hz, 1H), 5.68 (s, 1H), 5.57 (s, 1H), 4.59 (d, J=2.9 Hz, 1H), 4.20-4.19 (m, 1H), 3.81-3.79 (m, 4H), 3.74 (s, 3H), 3.20-3.18 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:15]([OH:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([F:18])=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:19])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>C1COCC1>[F:1][C:2]1[C:15]([O:16][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([F:18])=[C:9]([O:17][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:10]=3)[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: COCCOCCl
Reactant: O=c1c2cc(F)c(O)cc2oc2cc(O)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1cc2oc3cc(OCOCCOC)c(F)cc3c(=O)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A cloudy solution of 8 (2.4 g, 9.1 mmol) in dry THF (50 mL) was treated with sodium hydride (1.1 g, 45.8 mmol) at 0° C. under an Ar atmosphere. The mixture was stirred at 0° C. for 30 min and then 2-methoxyethoxymethyl chloride (5.2 mL, 45.8 mmol) was added. The mixture was stirred at 0° C. for an additional 30 min and then warmed to room temperature overnight. The reaction mixture was cooled to 0° C., quenched with 1M citric acid (50 mL), and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:1:0.4 to yield 2.6 g (65%) of 9 as a white solid. Rf=0.47 (in CH2Cl2/hexane/EtOAc=1:1:0.4); 1H NMR (300 MHz, CDCl3) δ7.91 (d, 2H, J=10.6 Hz), 7.28 (d, 2H, J=6.5 Hz), 5.46 (s, 4H), 3.91 (m, 4H), 3.60 (m, 4H), 3.39 (s, 6H); 13C NMR (75 MHz, CDCl3) 6174.4, 153.3, 153.2, 151.4, 151.0, 150.9, 148.2, 115.2, 115.1, 111.8, 111.6, 104.8, 94.2, 71.3, 68.6, 59.0; 19F NMR (282 MHz, CDCl3) δ −137.0 (dd, 2 F); mass spectrum, calculated for C21H22F2O8 (MH+) 441.1, Found 441.0.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[N:9]3[C:12]([CH2:15]O)=[N:13][N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:4]=2[CH:3]=1.C([N:26](CC)CC)C>C(Cl)(Cl)Cl>[NH2:26][CH2:15][C:12]1[N:9]2[C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:6][CH2:7][C:8]2=[N:14][N:13]=1
Reactant: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.75 g of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol is dissolved in 25 ml of absolute chloroform and there is added thereto 0.7 g of triethylamine and 0.6 g of methanesulphochloride. The mixture is stirred for 2.5 hours at 25° C., then washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The resulting oily methanesulphonic acid ester of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol is dissolved in 10 ml of dimethylformamide and the solution added dropwise at 0°-5° C. to a solution of 1 ml of liquid ammonia in 5 ml of dimethylformamide. The mixture is stirred for 2 hours at room temperature and then partitioned between saturated sodium chloride solution and methylene chloride. The organic phase is dried and evaporated and the residue recrystallized from ethanol. There is obtained 9-aminomethyl-2-chloro- 4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine of melting point 190°-192° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10])=[O:26]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: O=C(NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1cccc(C(F)(F)F)c1)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3-trifluoromethyl-benzoic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl>C(O)CCCC>[CH2:6]([O:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:5][CH2:4][CH2:9][CH3:8]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCCCCO
Product: CCCCCOC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
A slurry of 32.1 g (0.15 mole) of p-carboxybenzenesulfonamide, methyl ester in 400 ml of n-pentanol was treated with 25 g of anhydrous hydrogen chloride and the mixture was heated at reflux temperature for 4 hr. The reaction was again treated by the slow addition of anhydrous hydrogen chloride during 8 hr of slow distillation. Approximately 150 ml of distillate was collected. The distillate was replaced in the reaction mixture with 150 ml of n-pentanol and the solution was heated at reflux for 66 hr. Excess pentanol and hydrogen chloride were removed by distillation under vacuum. The residue wad crystallized from a mixture of 350 ml of ethyl acetate and 500 ml of petroleum ether to give 22.0 g (54%) of white flakes, mp 96°-98° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]([F:28])([F:27])[C:10]1[C:25]([Cl:26])=[CH:24][C:13]2[C:14](=O)[CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[S:18][C:12]=2[CH:11]=1.O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:8][C:9]([F:28])([F:27])[C:10]1[C:25]([Cl:26])=[CH:24][C:13]2[C:14]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[S:18][C:12]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2ccccc2Sc2cc(C(F)(F)F)c(Cl)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(C(F)(F)F)c(Cl)cc32)CC1
Yield: 88 %

Procedure:
1-Methylpiperazine (8.0 g) was added to a solution of 7-trifluoromethyl-8-chlorodibenzo(b,f)thiepine-10(11H)-one (the preparation of which is described in the preceding Example) (5.17 g) in benzene (40 ml). Then, titanium tetrachloride (1.63 g) in benzene (10 ml) was added dropwise, the mixture refluxed for 24 hours while stirring, cooled and decomposed with water (60 ml). The separated solid was filtered and washed with benzene and water. The benzene layer of the filtrate was separated, washed with water, filtered with charcoal and dried over magnesium sulfate. Evaporation of the benzene yielded 5.68 g (88%) of the crude enamine base, named in the heading of this Example. Neutralization of this base with methanesulfonic acid in ethanol, followed by addition of ether, yielded the crystalline methanesulfonate which crystallized from acetone as a monohydrate; m.p. 267°-270° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, MsCl (13.9 mL) was dropwise added to a suspension of 2-(4-nitrophenyl)ethanol (25.0 g) and Et3N (31.3 mL) in CHCl3 (including amylene, 625 mL) over 10 minutes under ice cooling, followed by stirring at room temperature for 2 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4, and then the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to yield the title compound (41.8 g, light yellow solid).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][C:34]([O:36]CC)=[O:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.S1C=CC=N1.N>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][C:34]([OH:36])=[O:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: CCOC(=O)Cn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Agent: N
Agent: c1cnsc1
Product: O=C(O)Cn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21

Procedure:
The desired compound was prepared according to the method of Example 49, step 2except substituting 3-(pyridin-3-yl)-7-[1-carboethoxymethyl-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole, prepared in step 1, for 3-(Pyridin-3-yl)-7-[1-(2-carbomethoxyethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-thiazole, m.p. 240°-249° C. 1H NMR (DMSO-d6, 300 MHz) δ4.45 (d, 1H, J=1.5 Hz), 4.65 (dd, 1H, J=1.5, 0.3 Hz), 4.84 (s, 2H), 6.7 (d, 1H, J=0.3 Hz), 6.78 (s, 1H), 6.87 (d, 1H, J=0.3 Hz), 7.3 (t, 2H, J=0.9, 1.5 Hz), 7.4-7.5 (m, 2H), 7.6-7.8 (m, 4H), 8.25-8.33 (m, 2H), 8.5-8.6 (m, 2H), MS (DCI/NH3) m/e 498 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([OH:13])[N:7]2[N:6]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:20]O>>[OH:13][C:12]1[N:7]2[N:6]=[C:5]([CH2:4][C:1]([O:3][CH3:20])=[O:2])[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=1
Reactant: CO
Reactant: Cc1cc(O)n2nc(CC(=O)O)nc2n1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1nc2nc(C)cc(O)n2n1

Procedure:
A solution of the product obtained in Step 2 (1.5 g) in 50 ml of methanol was cooled to 0° C., 24 ml of thionyl chloride was added dropwise to this solution at that temperature, and the mixture was refluxed for 1.5 hours. After removing the solvent by distillation under reduced pressure, the residue was recrystallized from ethyl acetate/ether, giving 1.5 g of the objective compounds.
Reaction SMILES: C([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)(C)(C)C.Cl[C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16]([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)=[O:17]
Reactant: CC(C)(C)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: COC(=O)Cl
Product: COC(=O)N1CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
reacting a mixture of 1-tertiarybutyl-3,3-dinitroazetidine and methyl chloroformate to form 1-(methyl oxycarbonyl)-3,3-dinitroazetidine;
Reaction SMILES: [O:1]1[C:5]2[C:6]3[C:7](=[CH:13][C:14]#[N:15])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1.N.C(O)C>C(O)C.[Co]>[O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH2:15])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1
Reactant: N#CC=C1CCc2ccc3ncoc3c21
Agent: [Co]
Agent: N
Solvent: CCO
Product: NCC=C1CCc2ccc3ncoc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.1 %

Procedure:
To a solution of (6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)acetonitrile (210 mg, 1.07 mmol) in ethanol (8 mL) were added Raney cobalt (2 g) and 2N ammonia/ethanol solution (4 mL), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0) to give the title compound (60.2 mg, yield 28%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6](C(O)=O)[C:5]([OH:11])=[CH:4][CH:3]=1>CO.S(=O)(=O)(O)O>[CH3:3][CH2:4][C:5]([O:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:6]=1)=[O:11]
Reactant: O=C(O)c1cc(I)ccc1O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(=O)Oc1ccc(I)cc1
Yield: 133.9 %

Procedure:
To a solution of 5-iodosalicylic acid (5.0 g, 18.94 mmol) in methanol (100 mL) was added a few drops of sulfuric acid. The reaction was stirred at reflux for 24 hours. The reaction solvent (methanol) was evaporated to small volume and water was added and extracted with dichloromethane. The organic layer was washed with 10% NaHCO3 solution, water and brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (3.5 g, 66.5%): 1H NMR (CDCl3) δ 3.96 (s, 3H), 6.78 (d, 1H), 7.70 (dd, 1H), 8.12 (d, 1H).
Reaction SMILES: C(OC(=O)C[N:6](C1CC1)C(=O)C1C=CC(OC(F)(F)F)=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1C=CC=C1C(Cl)=O.[CH2:42]([O:44][C:45](=[O:71])[CH:46]([N:54]([CH:68]1[CH2:70][CH2:69]1)[C:55](=O)[C:56]1[CH:61]=[CH:60][C:59]([O:62][C:63]([F:66])([F:65])[F:64])=[CH:58][CH:57]=1)[C:47]([C:49]1[O:50][CH:51]=[CH:52][CH:53]=1)=O)[CH3:43].FC(F)(F)C([O-])=O.[NH4+]>C1COCC1.CCO>[CH2:42]([O:44][C:45]([C:46]1[N:54]([CH:68]2[CH2:70][CH2:69]2)[C:55]([C:56]2[CH:61]=[CH:60][C:59]([O:62][C:63]([F:66])([F:65])[F:64])=[CH:58][CH:57]=2)=[N:6][C:47]=1[C:49]1[O:50][CH:51]=[CH:52][CH:53]=1)=[O:71])[CH3:43]
Reactant: CCOC(=O)C(C(=O)c1ccco1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(Cl)c1ccco1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccco2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Under argon, a solution of 1.071 g (3.23 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) in 10.0 ml of THF was added drop by drop to 3.5 ml of LiHMDS (solution 1M in THF, 3.5 mmol) cooled to −70° C. The reaction mixture was stirred for 10 min at −70° C. and for 1 hour at −30° C. Then, a solution of 0.167 g (1.28 mmol) of furan-2-carbonyl chloride in 10.0 ml of THF was added drop wise at −30° C. and the reaction mixture was stirred for 1 hour at −30° C. and then allowed to reach RT over 2 hours. The brown solution was partitioned between a sat. NH4Cl solution and EtOAc. The organic phases were washed with brine and the aqueous phases were extracted with EtOAc. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/n-heptane 1:1) to give 0.3 g of a 1:2 mixture of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester and 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-furan-2-yl-3-oxo-propionic acid ethyl ester. This mixture (0.30 g, max. 0.47 mmol) and 0.368 g (2.81 mmol) of ammoniumtrifluoroacetate were stirred for 10 min in 5 ml EtOH at room temperature; then, the solvent was evaporated and the brown oil was heated at 110° C. over night. The reaction mixture was cooled to RT and partitioned between CH2Cl2 and sat. NaHCO3 solution, the aqueous phase was extracted with CH2Cl2. The organic layers were dried over magnesium sulfate, evaporated and chromatographed (silica gel, EtOAc/n-heptane 1:4) to afford 0.098 g (49%) of the title compound as white powder. MS: 407.2 (MH+).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[C:12]1([C:22](O)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc2ccccc12
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc2ccccc12

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 1-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.94-2.71 (m, 7 H), 3.46-3.93 (m, 6H), 4.56 (s, 1H), 7.50-7.59 (m, 3H), 7.61-7.68 (m, 1H), 7.90-7.96 (m, 1H), 7.97-8.03 (m, 1H), 8.11-8.18 (m, 1H); MS (APCI/NH3) m/z 307 (M+H)+.